Prostanoids in cardiac and vascular remodeling

Abstract

Prostanoids are biologically active lipids generated from arachidonic acid by the action of the cyclooxygenase (COX) isozymes.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular (CV) adverse effects, including myocardial infarction, stroke, hypertension, and heart failure (HF). While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less it is known about the link between NSAIDs and HF risk. Current evidence indicates that NSAIDs may increase the risk for HF by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli.

This review will summarize current knowledge of the role of the different prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

Graphical Abstract

Effects of prostanoids in myocardial and vascular remodeling. Activation of the prostanoid receptors may alleviate (↓) or worsen (↑) the clinical consequences of adverse myocardial remodeling (cardiac dysfunction, cardiac fibrosis and hypertrophy, arrhythmia) and vascular remodeling (atherosclerosis, aneurysm formation, vascular hyperplasia, and stiffness). Created with Biorender.com.

Introduction

Prostanoids are bioactive lipid mediators that act locally to mediate a diverse range of physiological and pathological processes.^{1, 2} They are oxygenated metabolites derived from arachidonic acid (AA), a 20-carbon polyunsaturated omega-6 (n-6) fatty acid. Free AA is metabolized by the sequential actions of prostaglandin G/H synthase, also known as cyclooxygenase (COX), isomerases and synthases. This results in the formation of prostanoids, including prostaglandins (PGs), prostacyclin (PGI₂) and thromboxane (Tx)A₂ (Fig. 1).³

Fig. 1. An overview of the arachidonic acid pathway.

Arachidonic acid, after is cleaved by cellular membranes the phospholipase A₂ enzymes, is metabolized by the cyclooxygenase enzymes (COX-1 and COX-2) to form the unstable metabolite, prostaglandin (PG)H₂. Tissue specific isomerases and synthases further metabolize PGH₂ to form the different prostanoids: PGI₂ (also known as prostacyclin), PGE₂, PGD₂, PGF_2α, and thromboxane (Tx)A₂. Prostanoids exert their biological effects by interacting with G protein coupled receptors: IPr, receptor for PGI₂; EPr, receptor for PGE₂; DPr, receptor for PGD₂; FPr, receptor for PGF_2α; TPr, receptor for TxA₂. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of both COX-1 and COX-2. Coxibs inhibit only the activity of COX-2. Created with Biorender.com.

COX-1 and COX-2 activity are inhibited by traditional (t) non-steroidal anti-inflammatory drugs (NSAID)s, like ibuprofen, naproxen and diclofenac, and NSAIDs purposely designed to inhibit COX-2 (coxibs), such as rofecoxib, celecoxib and valdecoxib (Fig. 1).

Despite NSAIDs’ efficacy in relieving pain and inflammation,⁴ their use is limited by rare but serious adverse events, including cardiovascular (CV) complications [e.g., myocardial infarction (MI), stroke, hypertension (HTN), and heart failure (HF)].^5–9 In addition to the suppression of COX-2 derived vasoprotective prostanoids that may increase the risk for atherothrombotic events and hypertension, NSAIDs may increase the risk for HF by impairing CV remodeling after ischemic and non-ischemic events. In response to a physiological (pregnancy, exercise, etc.) or pathological stimulus (ischemic event, pressure or volume overload, hemodynamic stress, etc.), the heart and the vasculature undergo adaptive remodeling as part of the healing process.¹⁰ The cellular, molecular and interstitial events associated with the adaptive remodeling determine changes in the size, mass, geometry and function of the heart and the vasculature. In contrast to adaptive remodeling, maladaptive remodeling occurs when the response is excessive and uncontrolled. Clinical consequences of maladaptive remodeling include cardiac dysfunction, cardiac fibrosis and hypertrophy, arrhythmia, atherosclerosis, aneurysm formation, vascular hyperplasia and stiffness.¹⁰ Many molecular mechanisms and therefore several potential molecular mediators are involved in this process, including, inflammatory mediators, reactive oxygen species, mitochondrial metabolites, energy metabolites, contractile proteins, neurohormonal mediators, calcium handling proteins, collagen fibers.¹⁰ The exact role of these mediators and the magnitude of their relative contribution remains to be established. Among the inflammatory mediators, prostanoids contribute to adverse remodeling by modulating the structural and functional changes occurring in the myocardium and/or vasculature in response to ischemic or non-ischemic events. In this review, we will outline the role of prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

COX-1 and COX-2 in the cardiovascular system

The COX enzyme exists as two isozymes, known as COX-1 and COX-2. COX-1 is constitutively expressed in most cell types and is responsible, in the main, for homeostatic functions. ¹ COX-2 is usually an inducible enzyme which is mostly expressed in the setting of inflammatory states.¹ COX-2 is also constitutively expressed in the brain, the vasculature, and the kidney. However, these distinctions between COX-1 and COX-2 are relative rather than absolute and their expression and function are very context-dependent. ^{1, 2} The COX enzymes convert AA into unstable cyclic endoperoxides, PGG₂ and PGH₂, which then are metabolized by tissue-specific isomerases and synthases into PGE₂, PGD₂, PGF_2α, PGI₂, and TxA₂. Receptors for PGE₂ (EPr 1–4), PGD₂ (DPr 1–2), PGF_2α (FPr), PGI₂ (IPr) and TxA₂ (TPr) are linked to G-proteins, the expression of which is also tissue and cell specific (Fig. 1).

Several genetic variants of COX-1 and COX-2 genes have been associated with CV disease (CVD). The COX-1 C50T single nucleotide polymorphism (SNP) reduces response to aspirin, but does not modify the risk of atherothrombotic events in Caucasians.^11,12 In a Swedish cohort, the COX-1 SNP rs883484 TT was associated with increased formation of PGF_2α, while the COX-1 SNP rs10306135 TT was associated with decreased formation of PGF_2α and lower prevalence of CVD.¹³ The COX-1 rs1330344 SNP CC genotype is associated with an increased risk of subsequent vascular events in Chinese patients with ischemic stroke treated with aspirin¹⁴ and with an increased risk of Kawasaki disease and coronary artery injury in Chinese children.¹⁵

There are more than 50 active SNPs in human COX-2, but most of them are in silent sites. The COX-2 rs20417 GC genotype reduces promoter activity¹⁶ and COX-2 expression¹⁴, and is associated with decreased CV risk in Caucasians.^17,18 In contrast, the same COX-2 SNP is associated with increased risk for MI in Chinese¹⁹ and for coronary artery disease in Koreans²⁰, and it is more common in African Americans with stroke.²¹ In addition, three SNPs (rs689466, rs2066826 and rs20417) in the COX-2 gene co-segregate with either coronary or carotid calcified plaque risk in diabetics in a Caucasian population.²² The COX-2 rs20417 SNP is associated with a reduced risk for major CV events and lower TxA₂ and PGI₂.²³ The COX-2 rs5277 C allele is associated with increased risk for coronary artery disease and adverse cardiac and cerebrovascular events after coronary artery bypass grafting in Chinese.²⁴ The COX-2 rs12042763 and rs689466 SNPs are associated with changes in blood pressure (BP) in response to a low-salt or high-salt diet (HSD) in Chinese adults.²⁵

These genome-wide association studies (GWASs) indicate that genetic variants in COX genes may influence the risk for CVD and the type of association is affected by genetic ancestry.

COX-1 and COX-2 in Myocardial Remodeling

COX-1 is the main isoform expressed constitutively in normal heart. COX-2 expression is increased in response to stressor events.² Myocardial COX-2 expression is higher in patients with cardiomyopathies compared to healthy subjects.²⁶ In rat heart, Cox-2 expression increases significantly with age, whereas Cox-1 expression remains unchanged, indicating a role for COX-2 in myocardial age-related remodeling.²⁷

Genetic disruption or pharmacological inhibition of COX-1 in mice increases cardiac ischemia/reperfusion (I/R) injury, due to reduction of the cardioprotective PGI₂ and PGE₂.²⁸ In contrast, Cox-1 and PGI₂ synthase (Pgis) overexpression confers protection against ischemic stroke and CV damage and prolongs lifespan.²⁹

In mice, conditioned by genetic background, prenatal genetic disruption of Cox-2 reduces the survival rate due to cardiorenal anomalies attributable to the absence of Cox-2 during development. Surviving Cox-2 knockout (KO) mice present myocardial fibrosis³⁰ and an exacerbation of reperfusion injury.²⁸ Adult Cox-2 deficient rats, but not Cox-1 deficient rats, exhibit myocardial fibrosis, a reduction of cardiac ATP and acetyl-CoA production, increased mortality and comparatively preserved ejection fraction (EF). Thus, while EF is reduced compared to WT rats, it is still above 50%.³¹ Similarly, mice with cardiomyocyte-specific deletion of Cox-2 (CM-Cox-2 KO) exhibit perivascular and interstitial myocardial fibrosis, hypertrophy, arrythmia, reduced exercise tolerance, while EF is preserved.³² Since BP is similar in WT and CM-Cox-2 KO mice, these data are consistent with a direct role of COX-2 in myocardial remodeling.³² In contrast, Cox-2 overexpression in cardiomyocytes confers cardioprotection against I/R injury perhaps due to increased PGE₂ both in ex vivo³³ and in vivo³⁴ models. However, these transgenic mice develop cardiac hypertrophy and activation of a fetal gene program, although cardiac function remains normal.³⁵

Mixed results arise from animal studies investigating the effect of NSAIDs in cardiac remodeling.² Consistent with the phenotype observed in rodents lacking Cox-2, mice treated with diclofenac present with impairment of diastolic, but not systolic function, reduced calcium transients and cardiac mitochondrial dysfunction.³⁶ DFU, a selective COX-2 inhibitor, reduces infarct size and improves ventricular performance in infarcted rats.³⁷ NS-398 and rofecoxib, two selective COX-2 inhibitors, do not affect infarct size, but they reduce cardiac hypertrophy and collagen deposition in murine heart post post-MI.³⁸ Celecoxib protects against abdominal aortic constriction-induced cardiac hypertrophy in rats.³⁹ Aspirin does not have an effect on cardiac remodeling and function after MI, but reduces the expression of pro-inflammatory cytokines in the infarcted heart.⁴⁰ Deleterious cardiac effects are reported with celecoxib and NS-398 in the late phase of ischemic preconditioning in rabbits,⁴¹ with celecoxib after MI in pigs⁴² and with rofecoxib after MI in hyperlipidemic mice.⁴³ These conflicting results may result from differences in experimental design (disease model, drug regimen, species, sex and genetic background).

In summary, COX-1 has a protective effect in myocardial remodeling, while the role COX-2 is more controversial (Table 1).

Table 1.

In vivo pre-clinical studies assessing the effect of cyclooxygenases in cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Cox-1 deletion Indomethacin Cox-2 deletion	Cardiac I/R	↓ Cardiac function		28
Mouse	Cox-1 and Pgis overexpression	Chemical-induced thrombosis AA-induced thrombotic heart arrest Ang II-induced peripheral reperfusion damage	↓ Acute thrombotic stroke ↓ Arterial arrest ↓ Vasoconstrictive damage ↑ Lifespan		29
Mouse	Cox-2 deletion		↑ Cardiac fibrosis ↓ Survival		30
Rat	Cox-1 deletion Cox-2 deletion		None ↓ Cardiac function ↑ Cardiac fibrosis ↓ Survival	↓ Cardiac energy metabolism	31
Mouse	Cardiomyocyte Cox-2 deletion		↓ Exercise tolerance ↑ Cardiac hypertrophy ↑ Cardiac fibrosis Arrythmia		32
Mouse	Cardiac Cox-2 overexpression	Cardiac I/R	↓ Infarct size	↑ PGE2	34
Mouse	Cardiac Cox-2 overexpression		↑ Cardiac hypertrophy	↑ PGE2	35
Mouse	Diclofenac		Diastolic dysfunction ↑ Cardiac fibrosis	↑ Mitochondrial oxidative stress ↑ Pro-inflammatory cytokines	36
Mouse	Cox-2 inhibitor (DFU) Aspirin	MI MI	↓ Infarcted size ↓ LV pressure Improved contractility None		37
Mouse	Cox-2 inhibitor (NS-398) Rofecoxib	MI	↑ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ TGF-β	38
Rat	Celecoxib	Abdominal aortic constrictions	↑ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ Inflammation (AKT/mTOR/NF-κB) ↓ Apoptosis (MDM2-p53) ↓ Oxidative stress (NRF-2)	39
Mouse	Aspirin	MI	None	↓TNFα ↓IL-1β	40
Rabbit	Cox-2 inhibitor (NS-398) Celecoxib	Late phase of ischemic preconditioning	↑ Myocardial stunning ↑ Infarct size		41
Pig	Celecoxib	MI	↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis ↑ Mortality	↓ Collagen fiber density	42
Mice	Rofecoxib	Hyperlipidemia (APOE*3Leiden mice) I/R	↓ Cardiac function		43

AA, arachidonic acid; AKT, protein kinase B; Ang II, angiotensin II; Cox, cyclooxygenase; IL, interleukin; I/R, ischemia reperfusion; LV, left ventricle; MDM-2, mouse double minute 2 homolog; MI, myocardial infarction; m-TOR, mammalian target of rapamycin; NF-Κb, nuclear Factor kappa B; NRF-2, nuclear factor erythroid 2-related factor 2; PGE₂, prostaglandin E₂; Pgis, prostacyclin synthase; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha.

COX-1 and COX-2 in Vascular Remodeling

In the vasculature, COX-1 and COX-2 are expressed in both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and the extent of this expression is modulated by pathophysiological conditions.² Human atherosclerotic vessels exhibit increased expression of both COXs, with COX-2 localized mainly in proliferating VSMCs, and macrophages.⁴⁴ High COX-2 and matrix metalloproteinase (MMP)-9 expression in macrophages in human atherosclerotic plaques are associated with an increased risk of cerebrovascular symptoms.⁴⁵ In mice, Cox-1 genetic deletion or pharmacological inhibition retards the development of atherosclerotic lesions ^46–48 and prevents the increase in BP in response angiotensin (Ang) II infusion.⁴⁹ In contrast, Cox-1 deletion in bone-marrow cells accelerates the development of early atherosclerotic plaques in hyperlipidemic mice.⁵⁰ Endothelial-specific Cox-1 deletion retards atherosclerosis, and reduces vascular inflammation and the contractile response to vascular pressors.⁵¹ Consistently, Cox-1 deletion or inhibition reduces endothelial-dependent contraction both in atherosclerotic and non-atherosclerotic arteries.⁵²

Although the use of NSAIDs increases the risk for CV events in humans,⁷ Cox-2 deletion or inhibition accelerates, leaves unaltered or retards lesion progression in mice.^53–61 Global postnatal deletion of Cox-2, generated to overcome the multiple abnormalities observed in the conventional Cox-2 KOs, and vascular Cox-2 deletion result in accelerated atherogenesis.^{62, 63} The deletion of Cox-2 in myeloid cells retards atherogenesis while its deletion in CD4⁺ T-cells has no detectable effect on lesion burden.⁶⁴ However, T-regulatory cells may stabilize atherosclerotic plaques by reducing the expression of COX-2 in vulnerable plaque and particularly in macrophages.⁶⁵

COX-2-derived prostanoids contribute to BP control by regulating vascular tone and renal sodium transport. Both tNSAIDs and coxibs may increase BP in normotensive individuals and in patients with HTN.^{66, 67} Although postnatal Cox-2-KO mice have normal BP,⁶² Cox-2 deletion or inhibition exaggerates HTN after Ang II infusion⁴⁸ or in response to low-salt or HSD.⁶⁸ Mice in which Cox-1 is placed under the Cox-2 promoter are hypertensive.⁶⁹ Vascular Cox-2 KO mice challenged with HSD also exhibit HTN.⁷⁰ The hypertensive phenotype consequent to Cox-2 deletion is consistent with the suppression vasorelaxant PGI₂ and PGE_2.

Overall, COX-1 has protective effect in vascular remodeling. The effect of COX-2 depends on the cell type in which it is expressed and the substrate re-diversion consequent to its deletion or inhibition (Table 2).

Table 2.

In vivo pre-clinical studies assessing the effect of cyclooxygenases in vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Cox-1 deletion	Atherosclerosis (ApoE KO) Carotid ligation	↓ Athero plaque formation ↓ Platelet-vessel wall interactions	↓ TxBM ↓ PGIM	46
Mouse	Cox-1 inhibitor (SC-560) TP antagonist (BM-573)	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation ↑ Plaque stability	↓ TxBM ↓ Vascular inflammation (CD40L)	47
Mouse	Cox-1 inhibitor (SC-560)	Atherosclerosis (ApoE KO)	↓ Athero plaque formation	↓ TxBM ↓ Vascular inflammation (CD40L) ↓ Apoptosis (Bax)	48
Mouse	Cox-1 deletion Cox-1 inhibitor (SC-58560) Cox-2 deletion Cox-2 inhibitor (SC58236)	Ang II infusion Ang II infusion	↓ Hypotension ↑ Hypertension	↑ Medullary PGI2 and PGE2	49
Mouse	Bone marrow Cox-1 deletion	Atherosclerosis (ApoE KO or Ldlr KO)	↑ Athero plaque formation	↑ Cox-2 expression in macrophages	50
Mouse	Bone marrow Cox-1 deletion	Atherosclerosis (ApoE KO)	↓ Athero plaque formation	↓ Inflammation (IL-6, VCAM, P-selectin)	51
Mouse	Cox-1 deletion	Atherosclerosis (ApoE KO)	↓ Athero plaque formation		52
Mouse	Cox-2 inhibitor (MF-tricyclic)	Atherosclerosis (ApoE KO)	↑ Athero plaque formation		53
Mouse	Cox-2 inhibitor (MF-tricyclic) Sulindac	Atherosclerosis (ApoE KO)	No effect on athero plaque formation		54
Mouse	Nimesulide Indomethacin	Atherosclerosis (Ldlr KO)	No effect on athero plaque formation ↓ Athero plaque formation	↓ PGIM ↓ Inflammation (sICAM-1, MCP-1) ↓PGIM ↓TxBM	55
Mouse	Celecoxib	Atherosclerosis (ApoE KO)	No effect on advanced athero plaque formation		56
Mouse	Rofecoxib Indomethacin Hematopoietic Cox-2 deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation		57
Mouse	Rofecoxib Cox-2 inhibitor (NS-398) Indomethacin Hematopoietic Cox-2 deletion	Atherosclerosis (ApoE KO)	↓ Athero plaque formation		58
Mouse	Celecoxib	Atherosclerosis (ApoE KO)	↓ Athero plaque formation	↓ Inflammation (ICAM-1, VCAM-1)	59
Mouse	Celecoxib Rofecoxib Naproxen	Atherosclerosis (ApoE KO)	No effect on initiation and progression of atherosclerosis		60
Mouse	Parecoxib	Atherosclerosis (ApoE KO)	↑ Athero plaque stability	↓ Inflammation (VSMCs, macrophages, collagen, MMPs)	61
Mouse	Postnatal Cox-2 deletion	Atherosclerosis (ApoE KO)	↑ Athero plaque formation Normal BP	↑ Inflammation (VSMCs, leukocytes)	62
Mouse	EC Cox-2 deletion VSMC Cox-2 deletion EC/VSMC Cox-2 deletion	Atherosclerosis (Ldlr KO)	↑ Athero plaque formation	↑ Inflammation ↑ TxBM ↑ Cox-2 expression in macrophages	63
Mouse	Macrophage Cox-2 deletion T-cell (CD-4+) Cox-2 deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation No effect on atherogenesis	↓ Inflammation ↑ Cox-2 expression in VSMCs	64
Mouse	Cox-2 deletion	LSD HSD	↑ Hypertension ↑ Hypertension		68
Mouse	COX-1>COX-2	HSD	↑ Hypertension	↓ PGI2 in renal medulla	69
Mouse	EC/VSMC Cox-2 deletion	HSD	↑ Hypertension	↓ PGIM ↓ NO	70

Ang II, angiotensin II; Apoe, apolipoprotein E; Athero, atherosclerosis; BAX, Bcl-2 Associated X-protein; BP, blood pressure; Cox, cyclooxygenase; EC, endothelial cell; HSD, high salt diet; ICAM, intracellular adhesion molecule; IL-6, interleukin-6; Ldlr, low density lipoprotein receptor; LSD, low-salt diet; MMP, metalloproteinase; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; PGI₂, prostacyclin; PGIM, urinary prostacyclin metabolite; TxBM, urinary thromboxane metabolite; VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cell.

PGI₂ in the cardiovascular system

PGI₂, synthesized mainly by COX-2 and the downstream enzyme PGIS, exerts its actions through the IPr which is expressed in many different tissues/cells including the heart and vasculature.^{3, 71} IPr can function as a homodimer or as a heterodimer with TPr.³

In humans, common variants in the PTGIS gene are associated with MI risk.⁷² The PTGIS rs5629 SNP is associated with MI in a Japanese population ⁷³ and with carotid artery or intracranial arterial stenosis in a Chinese population,⁷⁴ while the PTGIS 1117CA SNP is associated with HTN.⁷⁵

The R212C SNP in the gene encoding for IPr, PTGIR, which blunts PGI₂ signaling, leads to accelerated atherothrombosis and it is associated with intimal hyperplasia of the common carotid arteries.^{76, 77} The PTGIR V53V/S328S SNPs are associated with platelet activation in patients with deep vein thrombosis.⁷⁷

Altogether, these genomic studies consistently indicate a cardioprotective role of the PGI₂ signaling pathway.

PGI₂ in Myocardial Remodeling

Mice lacking the IPr develop salt-sensitive HTN, cardiac hypertrophy and fibrosis.⁷⁸ Increased cardiac fibrosis is also observed in hypercholesterolemic IPr KO mice infused with Ang II.⁷⁹ Moreover, IPr KO mice present an increased hypertrophic response to aortic banding⁸⁰ and infarct size following I/R⁸¹, while myocardial tension and coronary flow rate are reduced.⁸¹ In contrast, beraprost, a PGI₂ analogue, reduces myocardial fibrosis and hypertrophy in salt-sensitive hypertensive rats treated with HSD.⁸² Similarly, ONO-1301, a synthetic PGI₂ agonist, reduces cardiac fibrosis, left ventricular dilation, and systolic dysfunction in response to pressure overload.⁸³ The antifibrotic effect of PGI₂ may be mediated via the TGF-β1 signaling pathway.^83–85 PGI₂ analogs increase myocardial contractility in the absence of changes in heart rate or BP, while leaving active relaxation and diastolic function intact in pigs.^{86, 87}

Inhaled iloprost, an analogue of PGI₂, improves myocardial performance and right ventricular systolic function during exercise by increasing LV global longitudinal strain reserve, and decreasing LV diastolic filling load and pulmonary hypertension⁸⁸ in HF patients with preserved EF (HFpEF).

In summary, these studies provide evidence for a direct protective role of PGI₂ against maladaptive myocardial remodeling and indicate that PGI₂ analogs may be beneficial for the treatment of HFpEF patients.

PGI₂ in Vascular Remodeling

PGI₂ is produced at low levels by the vasculature of healthy subjects, but its levels are significantly increased as a constraint on accelerated platelet vascular interactions in atherosclerotic patients.^44,89

IPr deletion accelerates atherosclerosis in hyperlipidemic mice. ⁹⁰ The atherosclerotic plaques of IPr KO mice present partial endothelial disruption, and increased platelet activation and leukocyte- EC interaction.⁹⁰ Moreover, IPr KO mice exhibit increased luminal stenosis following carotid vascular injury due to neointimal proliferation.⁹¹ Likewise, IPr deletion or COX-2 inhibition increases vascular hyperplasia in response to hemodynamic stress.⁹² In contrast, gene transfer of human PGIS into endothelium-denuded carotid arteries of rats increases PGI₂ production and reduces the neointimal-medial ratio.⁹³ Similarly, a PGI₂ analogue reduces intimal thickness in arterial anastomoses in hyperlipidemic rabbits.⁹⁴

In the presence of a dysfunctional IPr or high concentrations of an IPr agonist, PGI₂ can also bind TPr_α, but not TPr_β, in human VSMCs, causing its inhibition.⁹⁵ Iloprost promotes VSMC proliferation and the switching to a synthetic phenotype in human cells lacking the IPr. These effects are prevented by the TPr antagonist S18886 or TPr knockdown, indicating a dependence on the TP receptor.⁹⁶ In vivo studies are necessary to confirm the functional effect of PGI₂ on TPr.

PGI₂ also plays an important role in controlling vascular homeostasis. Basal BP is similar in IPr KO mice and their WT controls.^{80, 97} In response to HSD, IPr KO mice may present increased or reduced BP, depending on the experimental conditions.^{78, 98–100} Iloprost mediates endothelium-dependent relaxations in the mouse vasculature via the activation of cGMP and cAMP pathways.¹⁰¹ Beraprost prevents vascular stiffness in elderly with cerebral infarction.¹⁰²

Overall, PGI₂ plays a beneficial effect against maladaptive vascular remodeling.

TxA₂ in the cardiovascular system

TxA₂ is highly unstable, rapidly hydrolyzed to the biologically inactive, more stable marker, TxB₂, itself subject to further metabolism. TxA₂ is produced mainly by platelet COX-1 and the downstream enzyme thromboxane synthase (TBXS), exerts its biological functions via TPr, which exists in two spliced isoforms in humans, TPr_α (the only isoform expressed in mice) and TPr_β.TPr can associate to form homo- and heterodimers. In addition, TPr_a can heterodimerize with IPr, which promotes a cAMP generation like IPr activation and relocation in lipid rafts.³ Other lipid mediators, like PGI₂, isoprostanes and hydroxyeicosatetraenoic acids, can activate the TPr at high concentrations in vitro and in vivo. ^{95, 103–104} Moreover, the inhibition of TBXS determines PGH₂ accumulation which can also activate TPr. Therefore, although the biological significance of TPr activation by different ligands is not completely understood, this may limit the therapeutic efficacy of TBXS inhibitors. Indeed, the TBXS inhibitor, dazmegrel, failed to advance in clinical development for the treatment of CVD.¹⁰⁵

There are genetic variants for TBXAS1, the gene encoding for TBXS, and TBXA2R, the gene encoding for TPr. Common SNPs in TBXAS1 gene are associated with MI risk,⁷² while the rs41708 SNP is associated with symptomatic carotid artery disease or intracranial arterial stenosis.^{74, 106} Several TPr variants are associated with changes in platelet function and CVD: the variant V80E is associated with inhibition of platelet activation, the variant rs1TXB131882 is associated with carotid plaque vulnerability,¹⁰⁶ the variant A160T is associated with platelet activation, ¹⁰⁷ and the variant rs13306046 is associated with BP reduction.¹⁰⁸

Collectively, GWASs reveal the importance of the TxA₂ signaling pathway in the CV system.

TxA₂ in Myocardial Remodeling

TPr deletion, TXBS inhibition or TPr antagonism limits infarct size in rodents after I/R in vivo.^109–111 Moreover, TPr deletion ameliorates cardiac hypertrophy and fibrosis caused by IPr deletion⁷⁸ and reduces lipopolysaccharide-induced tachycardia.¹¹² TPr antagonism reduces the pressor response to electrically-induced muscle contraction in rats with HF¹¹³ and protects from right ventricular pressure overload. ^{114, 115} In contrast, a TPr agonist evokes ventricular arrythmia in anesthetized rabbits.¹¹⁶

In patients with HF, urine TxB₂ metabolite levels are independently associated with risk of death and the need for transplant or mechanical support.¹¹⁷

Altogether, TxA₂ contributes to CVD by favoring adverse cardiac remodeling, in addition to inducing platelet aggregation (Table 5).

Table 5.

In vivo pre-clinical studies assessing the effect of thromboxane A₂ in cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Rat	TBXS inhibitor (U-63,557A) TPr antagonist (SQ-29,548)	I/R	↓ Infarct size	↓ Neutrophil infiltration	109
Mouse	TXBS deletion TPr deletion	I/R	↓ Infarct size	Restoration microcirculation	110
Rat	IPr agonist/TXBS inhibitor (ONO-1301)	I/R	↓ Infarct size ↓ Cardiac fibrosis	↑ Hepatocyte growth factor	111
Mouse	TPr deletion FPr deletion	LPS	↓ Tachycardia		112
Rat	TPr antagonist (daltroban)	MI	↓ Exercise pressor reflex		113
Mouse	TPr antagonist (CPI211)	Pressure overload (Pulmonary artery banding)	↓ Cardiac fibrosis ↓ Cardiac hypertrophy	↓ TGF-β signaling.	114
Mouse	TPr antagonist (NTP42)	Pulmonary hypertension (monocrotaline) Pressure overload (Pulmonary artery banding)	↓ Cardiac fibrosis ↓ Cardiac hypertrophy		115
Rabbit	TPr agonist (U-46619)		Arrhythmia		116

IPr, prostacyclin receptor; I/R, ischemia reperfusion; LPS, lipopolysaccharide; MI, myocardial infarction; PGI₂, prostacyclin; TGF-β, transforming growth factor-beta; TPr, thromboxane A₂ receptor; TXBS, thromboxane A₂ synthase.

TxA₂ in Vascular Remodeling

COX-1 dependent TxA₂ formation is increased in subjects with severe atherosclerosis reflecting accelerated platelet-endothelium interactions.^{44, 89, 118} Consistently, deletion or blockade of TPr delays atherogenesis in hyperlipidemic mice or in diabetic mice.^{90, 119–121} Moreover, TP antagonism or TBXS inhibition decreases atherogenesis, delays progression of established atherosclerotic lesions, decreases BP, and improves vascular dysfunction in hyperlipidemic mice. ^122–124 The role of TxA₂ in atherosclerosis is mediated by the expression of TPr in VSMCs but not in ECs or in bone marrow cells.^{125, 126}

Genetic deletion or pharmacological blockade of the TPr attenuates the response to vascular injury in mice.⁹¹ TPr KO mice exhibit reduced neointimal hyperplasia in response to COX-2 inhibition or carotid ligation. ⁹² Furthermore, Tbxs and TPr KO mice have a reduced infarct size after I/R and chemical-induced vascular injury due to reduced oxidative damage.¹²⁷ Inhibition of TBXS or TPr blockade does not affect baseline BP. However, TPr KO mice have a reduced hypertensive response to Ang II and L-NAME, suggesting an interaction between the TxA₂ and Ang II/nitric oxide (NO) vaso-responsive pathways.^128–130 Deletion of TPr in VSMCs reduces HTN and aortic remodeling in response to Ang II, but not in unchallenged mice.¹³¹ Moreover, a TPr antagonist prevents the development of aortic hyperplasia and vascular fibrosis in spontaneously hypertensive stroke-prone rats. ¹³²

In summary, the Tbxs-TxA₂-TPr pathway has a deleterious effect in vascular remodeling (Table 6). In contrast to TBXS inhibition, TPr blockade could represent a good therapeutical target for the treatment of atherosclerosis progression, vascular injury and HTN. Clearly, the competition is low-dose aspirin and an advantage depends, at least to some extent, on the activation of TPr by non – canonical ligands, like the isoprostanes, without any impact on biosynthesis of PGI₂. Currently, the TPr antagonist ifetroban is under clinical development for several therapeutic indications, including CVD (NCT03962855).

Table 6.

In vivo pre-clinical studies assessing the effect of thromboxane A₂ in vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	TPr antagonist (nstpbp5185)	Atherosclerosis (ApoE KO)	↓ Athero plaque formation	Anti-inflammatory (↓ IL-6, ↓TNF-a) Antioxidative activity (↑ PON-1 activity) Antiplatelet activity (↓ TxA2)	119
Mouse	TPr antagonist (S18886)	Atherosclerosis (Apobec-1/Ldlr KO)	↓ Athero plaque formation No effect on athero regression		120
Mouse	TPr antagonist (S18886)	Diabetes and Atherosclerosis (ApoE KO + streptozotocin)	↓ Athero plaque formation	↓ Endothelial dysfunction (↑ eNOS ↓ ICAM-1 ↓ nitrotyrosine ↓ AGEs)	121
Mouse	TXBS inhibitor/TPr antagonist (BM-573)	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation ↓ Athero plaque progression		122
Mouse	TXBS inhibitor/TPr antagonist (BM-573) Aspirin	Atherosclerosis (ApoE KO)	↓ Athero plaque formation No effect	↓ ICAM-1 ↓ VCAM-1	123
Mouse	TXBS inhibitor/TPr antagonist (BM-573)	Atherosclerosis (ApoE KO)	↑Endothelial relaxation ↓Blood pressure	↑ NO bioavailability ↓ Oxidative stress	124
Mouse	EC TPr deletion VSMC TPr deletion 8-iso-PGF2α	Atherosclerosis (Ldlr KO)	No effect ↓ Athero plaque formation ↓ Athero plaque formation		125
Mouse	Bone marrow TPr KOs into WTs Bone marrow TPr KOs into TPr KOs	Atherosclerosis (ApoE KO)	No effect ↓ Athero plaque formation		126
Mouse	Txbs deletion TPr deletion Txbs TPr deletion Aspirin	Vascular injury I/R	↑ Microvascular function ↓ Infarct size	↓ Oxidative damage (↑ NO ↓ IL-1β Apoptosis)	127
Mouse	TPr deletion	Hypertension (L-NAME + HSD)	↓ BP ↓ Cardiac hypertrophy ↑ Kidney hypertrophy		128
Mouse	TPr deletion Cox-1 deletion	Hypertension (AngII)	↓blood pressure ↓cardiac hypertrophy (C57BL/6)		129
Mouse	TPr agonist (U-46619)	Vascular hyporesponsiveness (LPS)	↑ Vascular tone	↓ iNOS-NO	130
Mouse	VSMC TPr deletion	Hypertension (AngII)	↓ BP ↓ Vascular remodeling		131
Rat	TPr antagonist (Terutroban)	Hypertension (Spontaneously hypertensive stroke-prone rats + HSD)	↓ Aorta hyperplasia ↓ Aortic fibrosis	↓ TGF-β ↓ Heat shock protein-47	132

Ages, advanced glycation end products; Ang II, angiotensin II; Apobec, apolipoprotein B mRNA editing catalytic polypeptide-like; Apoe, apolipoprotein E; Athero, atherosclerosis; BP, blood pressure; Cox, cyclooxygenase; EC, endothelial cell; eNOS, endothelial nitric oxide; HSD, high salt diet; ICAM, intracellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide; I/R, ischemia/reperfusion; Ldlr, low density lipoprotein receptor; L-NAME, N (ω)-nitro-L-arginine methyl ester; LPS, lipopolysaccharide; NO, nitric oxide; PON-1, paraoxonase-1; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; TPr, thromboxane receptor; TxA₂, thromboxane A₂; TXBS, thromboxane A₂ synthase; VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cell.

PGE₂ in the cardiovascular system

PGE₂ is formed from PGH₂ by the action of three different synthases: microsomal PGE₂ synthase (mPGES)-1, mPGES-2 and cytosolic PGES (cPGES).³

PGE₂ is synthetized in many different cell types and, like PGD₂ and PGF_2α, it is inactivated by 15-hydroxyprostaglandin dehydrogenase, resulting in 15-keto-PGE₂.³ PGE₂ exerts its biological function via binding to four EPrs which activate different cellular signaling pathways.

Only genetic variants for PTGER2, the gene encoding for EPr2, has a recognized association with with CVD. The PTGER2 2–1-1 haplotype is associated with reduced risk of MI and the 2–2-1 haplotype with reduced risk of ischemic stroke.¹³³ Moreover, the PTGER2 rs17197 SNP AA genotype is more frequent in subjects with essential HTN in men¹³⁴ and the PTGER2 rs708494 SNP GG genotype is less common in subject with acute coronary syndromes than in those with stable coronary disease.¹³⁵

The current GWASs provide only a partial understanding of the complex role played by PGE₂ signaling in the cardiovascular system.

PGE₂ in Myocardial Remodeling

There are conflicting data on the role of PGE₂ in I/R and MI resulting from different experimental conditions. Global mPGES-1 deletion exacerbates I/R injury due to impairment of the cardiac microcirculation and increased inflammation.¹³⁶ Global or bone marrow-derived myeloid cell mPGES-1 deletion impairs cardiac function and induces cardiac hypertrophy in infarcted mice, ^{137, 138} however only the deletion of the enzyme in myeloid cells increases mortality.¹³⁸ In both genetic models, COX-dependent inflammatory cell infiltration in the myocardium contributes to the maladaptive remodeling consequent to mPGES-1 deletion. In contrast, mPGES-1 deletion in myeloid cells improves the post-MI survival rate without affecting cardiac function, fibrosis, hypertrophy and infarct size.¹³⁹ mPGES-1 inhibition, but not celecoxib, improves cardiac fibrosis and reduces infarct size after MI,¹⁴⁰ due to the shunting of PGH₂ to the cardioprotective PGI₂. ^{140, 141}

The effect of PGE₂ in adult myocardium is mediated mainly by EPr2, EPr3 and/or EPr4.³

EPr2 deletion exacerbates myocardial injury after MI by reducing inflammatory macrophages in the infarcted heart, and thereby impairing cardiac repair. ¹⁴²

EPr3 deletion in macrophages retards the healing process after MI by reducing neovascularization in peri-infarct zones.¹⁴³ EPr3 overexpression in cardiomyocytes reduces fibrosis and inflammatory cells infiltration in the infarcted heart, without affecting infarct size and cardiac hypertrophy.¹⁴⁴ In contrast, EPr3 overexpression globally or in cardiomyocytes reduces cardiac function, and increases cardiac hypertrophy and fibrosis after I/R.^{144, 145} EPr3 agonists protect against I/R injury in several animal models. ^146–147

Global and endothelial specific EPr4 deletion exacerbate infarct size after I/R^{136, 148} and in the late phase of ischemic preconditioning.¹⁴⁹ Consistently, EPr4 agonists reduce infarct size after I/R.^{148, 150} EPr4 deletion in cardiomyocytes or EPr4 overexpression reduces cardiac hypertrophy and fibrosis after MI,^{151, 152} but the former worsens cardiac function ¹⁵¹ while the latter improves systolic function post infarction.¹⁵²

In non-ischemic animal models, the role of PGE₂ in cardiac remodeling varies, depending on the type of insult. Exogenous PGE₂ alleviates isoproterenol-induced cardiac failure, hypertrophy, and fibrosis via inhibition of TGF-β1-GRK2 interaction.¹⁵³ mPGES-1 deletion worsens LV function and hypertrophy in response to Ang II.¹⁵⁴ In contrast, mPGES-1 deletion prevents myocardial fibrosis in mice treated with isoproterenol and reduces cardiac hypertrophy¹⁵⁵ and fibrosis in mice on high fat diet (HFD).¹⁵⁶ EPr3 KO mice and EPr4 KO mice fed on HFD reveal maladaptive remodeling, characterized by hypertrophy ad fibrosis.^157,158 Aged EPr4 KO male mice develop increased interstitial fibrosis, reduced LV function and dilated cardiomyopathy compared to sex- and age-matched control mice.¹⁵⁹ An EPr4 agonist reduces myocardial fibrosis in response to pressure overload¹⁶⁰ and reduces myocardial fibrosis, hypertrophy and inflammation after myocarditis.^161,162

PGE₂ also regulates cardiac contractility: it reduces cardiac contractility via the EPr3 receptor ¹⁶³ and increases it via the EPr4 receptor. ¹⁶³

PGE₂ may also play a role in cardiac regeneration. PGE₂ regulates stem cell activity directly through the EPr2 or indirectly by impacting the micro-environment. ¹⁶⁴

In summary, these studies establish that PGE₂ has diverse and contrasting effects in myocardial remodeling, depending on which receptor subtype is activated and which cell-type is involved.

PGE₂ in Vascular Remodeling

In the vasculature, PGE₂ is synthetized by ECs, VSMCs and fibroblasts by cPGES and mPGES-2 at baseline and by mPGES-1 after an insult.¹⁶⁵

Human symptomatic atherosclerotic plaques exhibit increased COX-2 and mPGES-1 expression which likely facilitates macrophage infiltration into the plaque shoulder.^{166, 167} Vulnerable plaques express preferentially EPr4.¹⁶⁸

In hyperlipidemic mice, deletion of mPGES-1 globally or in myeloid cells, retards atherosclerosis in hyperlipidemic mice,^169–170 due to rediversion to PGI₂ with a consequent reduction in oxidative stress.^170–171 In contrast, deletion of mPGES-1 in VSMCs does not influence atherogenesis.¹⁷⁰

PGE₂ produced by atherosclerotic plaques can activate platelets via the EPr3. Thus, atherothrombosis induced in vivo by mechanical rupture of the plaque is drastically decreased when platelet EPr3 is deleted.¹⁷² Deletion of EPr4, but not of EPr2, in hematopoietic cells suppresses atherosclerotic plaque formation by promoting apoptosis.¹⁷³ EPr4 deletion in myeloid cells does not impact the size or cellular composition of the atherosclerotic plaques in diabetic mice despite reducing pro-inflammatory cytokines. ¹⁷⁴ In contrast, EPr4 deletion in bone marrow has no effect on early atherogenesis but enhances local inflammation and alters lesion composition in established atherosclerosis. ¹⁷⁵

In addition to atherogenesis, PGE₂ also mediates vascular remodeling after injury. Deletion of mPGES-1 globally¹⁷⁶ or in myeloid cells attenuates neointimal hyperplasia after vascular injury,¹⁷⁷ while deletion of mPGES-1 in vascular cells promotes the proliferative response.¹⁷⁷ Global deletion of EPr3,¹⁷⁸ deletion of EPr4 in VSMC¹⁷⁹ or EPr4 agonists¹⁸⁰ restricts neointima formation in injured vessels. In contrast, global deletion of EPr2,¹⁸¹ deletion EPr4 in ECs,¹⁸⁰ overexpression of EPr3 globally¹⁷⁸ or of EPr4 in VSMCs¹⁷⁹ promotes neointimal hyperplasia after vascular injury.

PGE₂ is also involved in vascular remodeling during aortic aneurysm (AAA) formation. In humans, COX-2, mPGES-1 and EPr4 expression are increased in AAA compared to non-diseased areas of the vasculature.^{182, 183} Deletion of mPGES-1 protects against Ang II-induced AAA by reducing VSMC proliferation and oxidative stress.¹⁸⁴ Similarly, pharmacological inhibition or genetic deletion of EPr4 attenuates aneurysm formation in mice.^{183, 185–186} On the contrary, EPr4 deletion in VSMCs exacerbates aortic dissection in response to Ang II¹⁸⁷ and Epr4 deletion in bone marrow cells accelerates aneurysm formation, by increasing vascular inflammation.¹⁸⁸ Mice overexpressing Epr4 in VSMCs present increased mortality following Ang II-infusion due to AAA formation.¹⁸⁹

PGE₂ also controls BP regulating relaxation and contraction of VSMCs and vascular stiffness.

The effect of mPGES-1 deletion on BP is highly dependent on the mouse genetic background and experimental conditions. The lack of mPGES-1 does not affect BP in unchallenged mice in all genetic backgrounds that have been tested. mPGES-1 KO mice on 129/Sv background develop HTN in response to HSD or Ang II infusion.^{190, 191} mPGES-1 KO mice on DBA/1lacJ background remain normotensive in response low-salt diet, DOCA salt or Ang II. ^191–193 mPGES-1 KO mice on mixed DBA/1lacJ × C57BL/6 background do not respond to HSD,¹⁹⁴ but they become hypertensive after Ang II infusion.¹⁹⁵ Deletion of mPGES-1 in myeloid or vascular cells does not impact BP either at baseline or in a hyperlipidemic state,¹⁷⁷ while deletion of mPGES-1 in hemopoietic cells induces salt-induced HTN.¹⁹⁶

EPr1 KO mice are hypotensive and present a blunted pressor response to acute and chronic Ang II infusion, low-salt diet, uni-nephrectomy and deoxycorticosterone acetate.^197–199 EPr1 antagonism reduces BP in hypertensive rats¹⁹⁷ and prevents collagen deposition and vascular stiffness in response to Ang II.²⁰⁰ EPr3 deletion or antagonism blunts the pressure response to Ang II infusion. ^201–202 EPr₂ KO mice present a modest HTN on regular diet and develop profound but reversible HTN in response to an HSD.²⁰³ Myeloid (LysM-Cre) EPr4 KO mice are normotensive on a regular diet and in response to dietary sodium changes or Ang II infusion,²⁰⁴ but macrophage (CD11b-Cre) EPr4 KO mice develop HTN in response to HSD. Deletion of EPr4 in bone-marrow cells evokes salt sensitive HTN.¹⁸⁸ SMC EPr4 KO mice present elevated BP in response to Ang II.¹⁸⁹ EC EPr4 KO mice are hypertensive, while mice overexpressing EPr4 in ECs are hypotensive both at baseline and in response to Ang II.²⁰⁵

In humans, mPGES-1 expression in abdominal fat positively correlates with systolic BP, intima-media thickness and vascular stiffness.²⁰⁶ Consistently, mPGES-1 deletion prevents cardiomyocyte hypertrophy, cardiac fibrosis, endothelial dysfunction, and vascular inflammation in mice on HFD, indicating a role for mPGES-1-dependent PGE₂ in obesity-induced vascular remodeling.²⁰⁶

Overall, these data are consistent with a direct role of PGE₂ in vascular remodeling in response to Ang II, HSD or HFD. The conflicting results of the pre-clinical studies likely reflect the divergent signaling activated by the different EPrs under different experimental conditions. mPGES-1 or EPr4 may represent potential therapeutic targets for the prevention or mitigation of maladaptive vascular remodeling.

PGF_2α in the cardiovascular system

PGF_2α is synthetized by the action of PGF₂ synthase (PGFS) acting on PGH₂ and from PGD₂ and PGE₂ by cytosolic PGD₂ 11-ketoreductase and PGE₂ 9-ketoreductase, respectively.³ PGF_2α exerts its effects via binding the FPr, but it can also activate TPr at high concentrations.³

The SNP rs10508293 in the gene encoding for PGF_2α synthase, aldo-keto reductase family 1 member C3 (AKR1C3), is associated with reduced risk for preeclampsia.²⁰⁷ The PTGFR rs12731181SNP AA genotype is associated with higher FPr expression in leukocytes and increased risk for essential HTN in a Han Chinese population. ²⁰⁸

In summary, these initial GWASs indicate a deleterious effect of PGF_2α signaling in the CV system.

PGF_2α in Myocardial Remodeling

In the heart, PGF_2α biosynthesis increases under stress conditions like hypoxia and hemodynamic stress. ^209–210

The expression of AKR1C3 in blood cells is altered in MI patients ^211–212 and AKR1C3 may regulate ferroptosis in the cardiomyocytes of patients who suffer an MI.²¹¹

PGF_2α levels are increased in MI patients after percutaneous coronary intervention. ²¹³

The FPr is expressed in the myocardium,²¹⁴ and its activation increases contractile force and has a trophic and a positive inotropic effect in both neonatal and adult rat cardiomyocytes, through both calcium dependent or independent mechanisms.²¹⁵ However, depending on the experimental conditions, PGF_2α can also have a negative ionotropic effect on cardiomyocytes.²¹⁶ FPr activation increases the biosynthesis of atrial natriuretic peptide (ANP) in cardiac muscle cells²¹⁷ and of collagen in cardiac fibroblast through a mechanism independent of transforming growth factor β.²¹⁸

In mice, deletion of Cox-2 in cardiomyocytes induces Cox-2 expression in cardiac fibroblasts, thereby augmenting PGF_2α formation and contributing to myocardial fibrosis and arrhythmogenesis observed in these mice.³² Rats treated with a PGF_2α analog exhibit cardiac hypertrophy and higher ANP levels.²¹⁷ FPr silencing reduces collagen expression and ameliorates myocardial fibrosis and cardiomyopathy in diabetic rats.²¹⁹ FPr deletion, similarly to TPr deletion, reduces inflammatory tachycardia in mice.²²⁰

Overall, these investigations provide initial evidence for a harmful effect of PGF_2α in myocardial remodeling, however additional studies in genetically modified mice lacking Akr1c3 or FPr are warranted.

PGF_2α in Vascular Remodeling

FPr is expressed in the endothelium and in VSMCs and its expression in the vasculature increases with aging.²²¹ FPr silencing improves age-related HTN, vascular fibrosis and oxidative stress by preventing upregulation of Src/PAI-1 signal pathway.²²²

FPr deletion reduces BP after Ang II or PGF_2α infusion and retards atherosclerosis through impairment of the renin-angiotensin-aldosterone system.²²³ Moreover, FPr dimerizes with the Ang II type 1 receptor in VSMCs, contributing to the regulation of BP.²²⁴

In rats, FPr silencing protects from diabetes-induced vascular remodeling, causing a reduction of medial thickness, collagen content, and elastin/collagen ratio.²²⁵

As for myocardial remodeling, additional in vivo studies are required to understand more completely the effect of PGF_2α in vascular remodeling.

PGD₂ in the cardiovascular system

PGD₂ is synthetized by hematopoietic- and lipocalin-type PGD₂ synthases (H-PGDS and L-PGDS, respectively).³ H-PGDS is localized to the cytosol of immune and inflammatory cells, whereas L-PGDS is expressed in several tissues and is secreted in the blood.²²⁶ L-PGDS, in addition to its enzymatic activity, functions as a carrier of extracellular lipophilic ligands, playing an important role in metabolism.²²⁷ PGD₂ biological activities are mediated through DPr1 and DPr2 or chemoattractant receptor-homologous molecule (CRTH2). 15-d-PGJ₂ is a metabolite of PGD₂ that binds DPr2 and, at orders of magnitude greater concentrations than its endogenous concentration, it also binds and activates PPARγ.³ The common SNP 111 A>C in the gene encoding for L-PGDS is associated with lower HDL levels and higher risk for carotid atherosclerosis in Japanese hypertensive patients.²²⁸ There are human genetic variants for DPr1 and DPr2 but they are not associated with CVD, but rather with asthma and allergic disease, indicating the important role of PGD₂ as immune regulator. Analysis of patients with sepsis revealed that, although PGD₂ is elevated in patients with sepsis of bacterial or viral origin, it has a relative selectivity for sepsis induced by SARS-CoV-2.²²⁹ Indeed, genetic deletion or pharmacological inhibition of DPr1 protects aged mice from lethal SARS-CoV-2 infection. ²³⁰

PGD₂ in Myocardial Remodeling.

In humans, L-PGDS gene expression is upregulated in the blood of infarcted patients²³¹ and L-PGDS levels correlate with the severity of coronary artery disease.²³² Serum L-PGDS levels increase after coronary angioplasty and negatively correlate with the reoccurrence of restenosis.²³³

Also in mice the expression of L-PGDS in the myocardium is increased under stress conditions like chronic hypoxemia²³⁴ and PGD₂ levels in plasma are reportedly elevated after MI.²³⁵ L-PGDS derived PGD₂ mediates the protective effect of glucocorticoids against myocardial I/R injury by the activation of PGD₂-DPr1-ERK1/2 signaling pathway²³⁶ or the transcription factor Nrf2 via FPr.²³⁷ Deletion of DPr1 in macrophages retards cardiac healing after MI by impairing M2 polarization and therefore the resolution of the inflammation post MI.²³⁸ Genetic deletion of DPr2 or DPr2 antagonism protects against MI by reducing ER stress-induced cardiomyocyte apoptosis.²³⁹ In contrast, DPr2 deficiency in fibroblasts exacerbates isoproterenol-induced myocardial fibrosis since ER-anchored DPr2 promotes collagen degradation in fibroblasts via binding to La ribonucleoprotein domain family member 6.²⁴⁰

Overall, DPr2 expressed on cardiomyocytes or cardiac fibroblasts has a divergent effect. Antagonizing DPr2 on cardiomyocytes may prevent ischemic-induced apoptosis in the heart. In contrast, DPr2 activation on fibroblasts may suppress stress-induced organ fibrosis.

More studies are required to unveil the role of DPr1 in myocardial remodeling.

PGD₂ in Vascular Remodeling.

L-PGDS levels are increased in patients with essential HTN and in hypertensive patients with atrial fibrillation.^241–242 Moreover, L-PGDS is expressed on the atherosclerotic plaque and its serum level correlates with the severity of coronary artery disease. ²³² Hyperlipidemic L-PGDS KO mice develop metabolic syndrome, fat deposition, thickening of the aortic media²⁴³ and accelerated atherosclerosis due to an increased inflammatory response.²⁴⁴ Moreover, L-PGDS, but not H-PGDS, deletion accelerates thrombogenesis and evokes HTN, due to its function as lipophilic carrier. ²⁴⁵ In neurogenic hypertensive rats, inhibition of L-PGDS reduces, while DPr1 antagonism augments Ang II-salt induced HTN.²⁴⁶

ApoE DPr1 KO mice infused with Ang II exhibit increased AAA formation and an exaggerated BP response. They also have accelerated atherogenesis and thrombogenesis.²⁴⁷ Since mouse platelets do not express DPr1, these phenotypes are a consequence of the lack of DPr1 in the vasculature. Consistently, deletion of DPr1 in VSMCs evokes HTN and thickening of the vasculature after Ang II infusion, due the lack of a protective role of DPr1 on VSMC phenotypic switching to myofibroblasts. ²⁴⁸ Genetic deletion of DPr1 or antagonism of DPr1 or DPr2 protects against Ang II-induced AAA and calcium chloride-induced AAA.²⁴⁹ Deletion of DPr1 in CD⁴⁺ T-cells aggravates, while DPr1 overexpression in CD⁴⁺ T-cells retards age-induced HTN by modulating vascular/renal superoxide production in male mice.²⁵⁰

In summary, DPr1 may serve as target for reducing age-related vascular diseases, including hypertension, atherosclerosis, and AAA.

Conclusions

Prostanoids play a complex and essential role in regulating myocardial and vascular remodeling.

In addition to increasing the risk of atherothrombotic events, prostanoid inhibition by NSAIDs may favor adverse remodeling of the CV system, contributing to the non-ischemic CV complications associated with the use of these drugs.

Nevertheless, increasing evidence supports the potential therapeutic value of targeting prostanoid synthases or their receptors for the treatment of CVD. Further studies in suitable animal models of human relevance, including age and sex as variables, are required to advance the rationale for clinical development of effective therapeutic strategies to prevent or mitigate adverse CV remodeling.

Table 3.

In vivo pre-clinical studies assessing the effect of prostacyclin in cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	IPr deletion IPr /TPr deletion	Normal diet LSD HSD Normal chow diet	↑ Hypertension ↑ Cardiac hypertrophy ↑ Cardiac fibrosis ↑ Hypertension		78
Mouse	IPr deletion	Hypercholesterolemia (ApoE KO) AngII	↑ Cardiac fibrosis	↓ cAMP ↓ CREB phosphorylation	79
Mouse	IPr deletion	Pressure overload (TAC)	Normotensive ↑ Cardiac hypertropy ↑ Cardiac fibrosis		80
Mouse	IPr deletion TPr deletion	I/R	↑ Infarcted area None		81
Salt-sensitive Dahl rat	PGI2 analog (Beraprost)	HSD	↑ Diastolic function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis ↑ Survival		82
Mouse	PGI2 analog (ONO-1301)	Pressure overload (TAC)	↑ Systolic function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ TGF-β-induced fibroblast-to-myofibroblast transition	83
Pig	PGI2 analogs (Epoprostenol, Iloprost)		↑ LV contractility		86
Pig	PGI2 analogs (Epoprostenol, Iloprost)		Preservation of EDP		87

Ang II, angiotensin II; Apoe, apolipoprotein E; cAMP, cyclic AMP; CREB, cyclic AMP-response element binding; EDP, end diastolic pressure; HSD, high salt diet; IPr, prostacyclin receptor; I/R, ischemia reperfusion; LSD, low-salt diet; LV, left ventricle; PGI₂, prostacyclin; TAC, transverse aortic constriction; TGF-β, transforming growth factor-beta; TPr, thromboxane A₂ receptor.

Table 4.

In vivo pre-clinical studies assessing the effect of prostacyclin in vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	IPr deletion TPr deletion	Atherosclerosis (ApoE KO)	↑ Athero plaque formation ↓ Athero plaque formation	↑ ICAM-1 ↓ PECAM-1	90
Mouse	IPr deletion TPr deletion TPr antagonist (S18886)	Vascular injury	↑ Vascular proliferation and platelet activation ↓ Vascular proliferation and platelet activation		91
Mouse	IPr deletion Nimesulide TPr deletion+ Nimesulide	Transplant arteriosclerosis Common carotid artery ligation	↑ Neo-intimal hyperplasia ↓ Blood flow No effect	↑ TxA2 ↑ 8, 12 –iso iPF2α-VI	92
Rat	Ptgis overexpression	Vascular injury (carotid balloon injury)	↓ Neo-intimal hyperplasia	↑ PGI2	93
Rabbit	PGI2 analogue (TRK-100)	Hypercholesterolemia (Diet+1% cholesterol) Re-anastomosis of abdominal aorta	↓ Intimal proliferation	↑ PGI2 ↓ TxA2	94
Mouse	IPr deletion	Regular chow diet	Normotensive Normal heart rate		97
Mouse	IPr deletion TPr deletion	Regular chow diet HSD Regular chow diet HSD	Hypotension Hypertension Normotensive Normotensive		98
Mouse	IPr deletion	HSD	Hypertension Cardiac fibrosis		99
Mouse	IPr deletion	Hypercholesterolemia (Ldlr KO) HSD	Hypotension (male mice) Normotensive (female mice)		100

Apoe, apolipoprotein E; Athero, atherosclerosis; HSD, high salt diet; ICAM, intracellular adhesion molecule; IPr, prostacyclin receptor; iPF, isoprostane F; Ldlr, low density lipoprotein receptor; PCAM-1, platelet endothelium cell adhesion molecule-1; PGI₂, prostacyclin; TxA₂, thromboxane A₂; TPr, thromboxane A₂ receptor.

Table 7.

In vivo pre-clinical studies assessing the effect of prostaglandin E₂ in cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Cox-1 deletion Ptges deletion EPr4 deletion EC EPr4 deletion	I/R	↑ Infarct size ↓ Cardiac function	↓ Microvascular perfusion ↑ Inflammation	136
Mouse	Ptges deletion	MI	↓ Systolic function ↓ Diastolic function ↑ Cardiac hypertrophy ↑ LV dilation ↓ LV contractile function		137
Mouse	Bone-marrow Ptges deletion	MI	↓ Systolic function ↓ Diastolic function ↑ Cardiac hypertrophy ↑ LV dilation ↑ Mortality	↑ Cox-1	138
Mouse	Myeloid cell Ptges deletion	MI	↓ Mortality		139
Mouse	mPGES-1 inhibitor (CIII) Celecoxib	MI	↓ Infarct size ↓ Fibrosis None	↑ Urinary PGI2 /PGE2 ratio ↓ Inflammation (↓IL-1β, IL-18, TNF-α, INF-γ)	140
Mouse	Ptges deletion + IPr antagonist	MI	↓ Mortality ↑ Infarct size		141
Mouse	EPr2 deletion	MI	↑ Infarct size ↑ Cardiac hypertrophy ↓ Cardiac function	↓ Inflammation	142
Mouse	Myeloid EPr3 deletion	MI	↓ Cardiac function	↓ Inflammation ↓ Angiogenesis ↓ TGFβ1-mediated cardiac repair	143
Mouse	Cardiomyocyte EPr3 overexpression	MI	↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis		144
Mouse	EPr3 overexpression		↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis	↑ Calcineurin activity ↑ NFAT activity	145
Rat Rabbit	EPr3 agonist (ONO-AE-248)	I/R	↓ Infarct size	Activation of PKC Opening of KATP channels	146
Minipig	EPr3 agonist (M&B 28.767)	I/R	↓ Infarct size ↓ Arrhythmia		147
Mouse	EPr4 deletion EPr4 agonist (4819-C)	I/R	↑ Infarct size ↓ Infarct size		148
Mouse	EPr4 deletion EPr4 agonist (AE1–329)	IPC+I/R I/R	No effect on infarct size ↓ Infarct size ↑ Cardiac function	↑ Akt signaling	149
Rat	EPr4 agonist (EP4RAG)	I/R	↓ Infarct size ↑ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ MCP-1	150
Mouse	Cardiomyocyte EPr4 deletion	MI	↓ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↑ Stat-3 signaling	151
Mouse	Cardiomyocyte EPr4 deletion	MI	↓ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↑ Stat-3 signaling	151
Mouse	EPr4 overexpression	MI	↑ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ Inflammation	152
Mouse	PGE2	HF (isoproterenol)	↑ Cardiac function ↓ Cardiac hypertrophy ↓ Cardiac fibrosis	↓ TGF-β1-GRK2 crosstalk	153
Mouse	Ptges deletion	Cardiac hypertrophy (Ang II)	↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis	↑ Apoptosis	154
Mouse	Ptges deletion	HF (isoproterenol)	↓ Cardiac fibrosis		155
Mouse	Ptges deletion	HFD	↓ Cardiac hypertrophy ↓ Cardiac fibrosis ↓ Endothelial dysfunction	↓ Inflammation	156
Mouse	EPr3 deletion		↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis	↓ MAPK/ERK pathway ↓ MMP-2 activity	157
Mouse	EPr4 deletion	HFD	↑ Cardiac hypertrophy ↑ Cardiac fibrosis ↓ Cardiac metabolism	↓ FOXO1/CD36 signaling axis	158
Mouse	Cardiomyocyte EPr4 deletion	Aging	↓ Cardiac function ↑ Cardiac hypertrophy ↑ Cardiac fibrosis in males but not females	↑ GDF-15 in the heart	159
Mouse	EPr4 agonist (ONO-0260164)	Cardiac hypertrophy (TAC)	↑ Cardiac function ↓ Cardiac fibrosis	↑ PKA ↓ TGF-β1 mediated collagen induction	160
Mouse	EPr4 agonist (ONO-0260164)	Autoimmune myocarditis	↑ Cardiac function ↑ LV contractility ↓ Cardiac fibrosis ↓ Cardiac hypertrophy	↑ TIMP-3/MMP-2 axis	161
Rat	EPr4 agonist (EP4RAG)	Autoimmune myocarditis	↑ Cardiac function ↓ Cardiac fibrosis	↓ CD4+ T-cells	162
Mouse	EPr2 deletion	MI	↓ Cardiac stem cells renewal ↓ Cardiac regeneration		164

AKT, protein kinase B; Ang II, angiotensin II; Cox, cyclooxygenase; EC, endothelial cell; HFD, high fat diet; ERK, Extracellular signal-regulated kinase; EPr, prostaglandin E receptor; FOXO, Forkhead box O; GDF15, growth/differentiation factor 15; GRK, G protein-coupled receptor kinases; IL, interleukin; IPC, ischemic preconditioning; INF, interferon; IPr, prostacyclin receptor; I/R, ischemia/reperfusion; LV, left ventricle; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; MMP, metalloproteinase; NFAT, Nuclear factor of activated T-cells; PGE₂, prostaglandin E₂; PGI₂, prostacyclin; PKA, protein kinase A; PKC, protein kinase C; Ptges, microsomal prostaglandin E synthase-1; STAT3, signal transducer and activator of transcription 3; TAC, transverse aortic banding; TGF-β, transforming growth factor-beta; TIM, tissue inhibitor of metalloproteinase; TNF-α, tumor necrosis factor-alpha.

Table 8.

In vivo pre-clinical studies assessing the effect of prostaglandin E₂ in vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Ptges deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation	↑ PGIM ↓ PGEM	169
Mouse	Myeloid cell Ptges deletion VSMC Ptges deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation None	↓ Oxidative stress	170
Mouse	IPr and Ptges deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation	↓ PGEM	171
Mouse	Platelet EPr3 deletion	Atherosclerosis (ApoE KO)	↓ Atherothrombosis		172
Mouse	Hematopoietic EPr2 deletion Hematopoietic EPr4 deletion	HFD	None ↓ Athero plaque formation	↓ PI3K/Akt and NF-kappaB pathways	173
Mouse	Myeloid cell EPr4 deletion	T1DM-accelerated atherogenesis	None		174
Mouse	Bone-marrow EPr4 deletion	Atherosclerosis (Ldlr KO)	No effect on athero plaque size Increased inflammatory cell infiltration	↑ MCP-1 ↑ INF-γ	175
Mouse	Ptges deletion	Femoral injury	↓ Neointimal area ↓ Vascular stenosis	↓ Tenascin-C	176
Mouse	VSMC Ptges deletion Myeloid Ptges deletion	Femoral injury	↑ Neointimal area ↓ Neointimal area	↑ Tenascin-C	177
Mouse	Cox-2 deletion EPr3 deletion Epr3 overexpression Cox-1>Cox-2	Femoral injury	↓ Neointimal area ↓ Vascular stenosis ↑ Neointimal area ↑ Vascular stenosis	↓ Phosphatidylinositol 3-kinase signaling	178
Mouse	VSMC EPr4 deletion VSMC EPr4 overexpression	Femoral injury	↓ Neointimal area ↑ Neointimal area	↑ Tenascin-C-PKA-mTORC1-rpS6	179
Mouse	IPr/Ptges deletion EC EPr4 deletion EPr4 agonist (AE1-329; Misoprostol)	Femoral injury	↑ Neointimal area ↓ Neointimal area		180
Mouse	EPr2 deletion	Femoral injury	↑ Neointimal area	↑ cyclin D1 ↑ PDGF-BB-signaling	181
Mouse	EPr4 antagonist (ONO-AE3-208) Partial EPr4 deletion	Aneurysm formation (ApoE KO+ AngII)	↓ Aneurism formation	↓ MMP activity	183
Mouse	Ptges deletion	Aneurysm formation (Ldlr KO+ AngII)	↓ Aneurism formation	↓ Oxidative stress	184
Mouse	EPr4 antagonist (ONO-AE3-208) Cox-2 KD	Aneurysm formation (ApoE KO+ AngII)	↓ Aneurism formation No effect on atherogenesis No effect	↓ MMP activity ↓ MIP-1α	185
Mouse	EPr4 antagonist (CJ-42794)	Aneurysm formation (ApoE KO+ AngII) Aneurysm formation (ApoE KO+ CaCl2)	↓ Aneurism formation	↓ MMP-2 activity ↓ IL-6	186
Mouse	VSMC EPr4 deletion	Aortic dissection model (AngII)	↑ BP ↑ Aortic dissection	↑ Vascular inflammation ↑ MMP activity	187
Mouse	Bone marrow EPr4 deletion	Aneurysm formation (Ldlr KO+ AngII)	↑ BP ↑ Aneurysm formation	↑ Vascular inflammation (↑ MCP-1; Apoptosis; Elastin fragmentation)	188
Mouse	VSMC EPr4 overexpression VSMC EPr4 deletion	Aneurysm formation (ApoE KO+ AngII) Aneurysm formation (AngII or CaCl2)	↑ Aneurysm formation ↑ Mortality ↑ BP ↓ Aneurysm formation	↑ MMP-9 activity ↑ IL-6	189
Mouse	Ptges deletion (DBA/1lacJ×C57BL/6)	HSD AngII	↑ BP	NO/cGMP pathway	190
Mouse	Ptges deletion (DBA/1lacJ) Ptges deletion (129/SvEv)	Unchallenged Hypertension (Ang II) Unchallenged Hypertension (Ang II)	Normotensive Mild hypertension Slightly hypertensive Severe hypertension	↑ TxBM	191
Mouse	Ptges deletion	Hypertension (DOCA-salt)	↑ BP	↑ Oxidative stress	193
Mouse	Cox-2 deletion Cox-2 inhibition IPr deletion Ptges deletion (DBA/1lacJ× C57BL/6)	Vascular damage Hypertension (Ang II)	↑ Thrombogenesis ↑ BP No effect		194
Mouse	Ptges deletion (DBA/1lacJ×C57BL/6)	Hypertension (Ang II)	↑ BP	↑ Oxidative stress	195
Mouse	Bone-marrow Cox-2 deletion Bone-marrow Ptges deletion	Hypertension (HSD)	↑ BP	↑ Renal inflammation	196
Rat Mouse	EPr1 antagonist (SC51322) EPr1 deletion	Spontaneously hypertensive rat Hypertension (Ang II)	↓ BP ↓ BP		197
Mouse	EPr1 deletion	Regular chow LSD	↓ BP		198
Mouse	EPr1 deletion	Hypertension (uninephrectomy, DOCA, Ang II)	↓ BP ↓ Mortality		199
Rat Mouse	Celecoxib EPr1 antagonist (SC19220)	Spontaneously hypertensive rat Hypertension (Ang II)	↓ Vascular stiffness ↓ Vascular dysfunction	↓ Vascular inflammation	200
Mouse	Epr3 deletion	Hypertension (Ang II)	↓ BP both at baseline and after Ang II	↓ Intracellular Ca 2+	201
Mouse	Epr3 antagonist (L798,106)	Hypertension (Ang II)	↓ BP ↑ Cardiac function		202
Mouse	Epr2 deletion	Regular chow Hypertension (HSD)	↑ BP		203
Mouse	Macrophage Epr4 deletion Kidney epithelial cell Epr4 deletion	Hypertension (HSD, AngII) Hypertension (HSD) Hypertension (AngII)	Normotensive Normotensive ↑ BP	↓ Natriuresis	204
Mouse	EC Epr4 deletion EC Epr4 overexpression	Regular chow HSD Regular chow HSD	↑ BP ↓ BP	↓ NO ↓ eNOS phosphorylation at Ser1177	205
Mouse	Ptges deletion	HFD	↓ Body weight ↓ Adiposity ↓ Endothelial dysfunction		206

Akt, protein kinase B; Ang II, angiotensin II; Apoe, apolipoprotein E; Athero, atherosclerosis; BP, blood pressure; Cox, cyclooxygenase; DOCA, deoxycorticosterone acetate; EC, endothelial cell; HFD, high fat diet; HSD, high salt diet; eNOS, endothelial nitric oxide synthase; EPr, prostaglandin E receptor; INF, interferon; IL, interleukin; IPr, prostacyclin receptor; Ldlr, low density lipoprotein receptor; LSD, low salt diet; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; MMP, metalloproteinase; m-TOR, mammalian target of rapamycin; NO, nitric oxide; PDGF, platelet derived growth factor; PGEM, urinary prostaglandin E metabolite; PGIM, urinary prostacyclin metabolite; PI3K, Phosphoinositide 3-kinase; PKA, protein kinase A; Ptges, microsomal prostaglandin E synthase-1; TGF-β, transforming growth factor-beta; TxBM, urinary thromboxane metabolite synthase; VSMC, vascular smooth muscle cell.

Table 9.

In vivo pre-clinical studies assessing the effect of prostaglandin F_2αin cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Rat	PGF2α analog (fluprostenol)		↑ Cardiac hypertrophy		217
Rat	FPr shRNA	Type 2 diabetes (HFD +Streptozotocin)	↓ Lipids ↓ Glucose ↓ Insulin ↓ Collagen	↓ PKC/Rho and Akt signaling	219
Mouse	TPr deletion FPr deletion	Inflammatory tachycardia (LPS)	↓ Tachycardia		220

AKT, protein kinase B; FPr, prostaglandin F receptor; HFD, high fat diet; LPS, lipopolysaccharide, PGF_2α, prostaglandin F_2α, PKC, protein kinase C; TPr, thromboxane receptor.

Table 10.

In vivo pre-clinical studies assessing the effect of prostaglandin F_2αin vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	FPr deletion	Atherosclerosis (Ldlr KO)	↓ Athero plaque formation ↓ BP	↓ inflammation (TNF-α; iNOS; TGF-β; macrophages) ↓ renin, angiotensin, and aldosterone	223
Rat	FPr shRNA	Type 2 diabetes (HFD +Streptozotocin)	↓ Medial thickness, collagen content, elastin/collagen ratio	↓ JNK phosphorylation	225

Athero, atherosclerosis; BP, blood pressure; FPr, prostaglandin F receptor; HFD, high fat diet; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; Ldlr, low-density lipoprotein receptor; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha.

Table 11.

In vivo pre-clinical studies assessing the effect of prostaglandin D₂ in cardiac remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Ptgds deletion+dexamethasone	I/R	Loss cardioprotective effect	↓ ERK1/2 signaling	236
Mouse	FPr deletion + dexamethasone	I/R	Loss cardioprotective effect	↓ NRF2 signaling	237
Mouse	Macrophage DPr1 deletion	MI	↓ Cardiac function ↑ Infarct size	↓ JAK2/STAT1 signaling ↓ Macrophages M2 polarization ↓ Inflammation resolution	238
Mouse	DPr2 deletion DPr2 antagonist (CAY10595)	MI	↑ Cardiac function ↓ Infarct size ↓ Fibrosis ↓ Hypertrophy ↓ Mortality	↓ ER stress-induced Cardiomyocyte apoptosis ↓ Caspase-12	239
Mouse	Fibroblast DPr2 deletion	Isoproterenol	↑ Fibrosis	↓ Reduced binding to La ribonucleoprotein domain family member 6	240

DPr, prostaglandin D receptor; FPr, prostaglandin F receptor; JAK2, Janus kinase 2; Ptgds, lipocalin prostaglandin d synthase; STAT1, signal transducer and activator of transcription 1.

Table 12.

In vivo pre-clinical studies assessing the effect of prostaglandin D₂ in vascular remodeling.

Specie	Intervention	Preclinical model	Phenotype	Mechanism	Ref.
Mouse	Ptgds deletion	HFD	↑ Glucose-in-tolerant ↑ Insulin-resistant ↑ Athero plaque formation ↑ Aortic thickening		243
Mouse	Ptgds deletion	Atherosclerosis (ApoE KO +HFD)	↑ Body weight ↑ Athero plaque formation	↑ Macrophage infiltration ↑ Inflammation (IL-1β, MCP-1)	244
Mouse	Ptgds deletion Hpgds deletion		↑ BP ↑ Thrombogenesis None		245
Rat	COX inhibitor Ptgds inhibitor (AT56) DPr1 antagonist (BWA868C)	Hypertension (HSD+ Ang II)	↓ BP ↑ BP		246
Mouse	DPr1 deletion	Atherosclerosis (ApoE KO) Aneurism formation (ApoE KO + AngII)	↑ Athero plaque formation ↑ Aneurysm formation ↓ Thrombogenesis (female mice)		247
Mouse	VSMC DPr1 deletion	Hypertension (Ang II)	↑ BP ↑ Vascular media thickness	↑ VSMC switch to myofibroblasts by impairing ↓ phosphorylation of MRTF by ROCK-1	248
Mouse	DPr1 deletion DPr1 antagonist (laropiprant) DPr2 antagonist (fevipiprant)	Aneurism formation (AngII + CaCl2)	↓ Aneurism formation	↓ MMP ↓ Elastin degradation ↓ Inflammation	249
Mouse	CD4+ T-cell DPr1 deletion CD4+ T-cell DPr1 overexpression	Aging	↑ BP ↓ BP	↓ Th1 activation ↑ NEDD4L-mediated T-bet degradation	250

Apoe, apolipoprotein E; Ang II, angiotensin II; Athero, atherosclerosis; BP, blood pressure; CaCl₂, calcium chloride, DPr, prostaglandin D receptor; Hpgds, hematopoietic prostaglandin D synthase; HSD, high salt diet; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MMP, metalloproteinase; MRTF, myocardin-related transcription factor)-A; NEDD4L, Neural precursor cell expressed developmentally downregulated gene 4-like; Ptgds, lipocalin prostaglandin d synthase; ROCK-1, Rho-associated kinase-1; VSMC, vascular smooth muscle cell.

Highlights.

• Prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli.

• COX-1 derived prostanoids have a protective effect in myocardium and vascular remodeling, while the effect of COX-2 derived prostanoids is more complicated. It depends on the cell type in which COX-2 is expressed and the substrate re-diversion consequent to its deletion or inhibition.

• The use of nonsteroidal anti-inflammatory drugs, which reduce the biosynthesis of prostanoids by inhibiting COX isozymes, is associated with an increased risk of cardiovascular events, including myocardial infarction, stroke, hypertension, and heart failure.

• Targeting specific prostanoid synthases or their receptors may represent a novel effective strategy to prevent or mitigate adverse cardiovascular remodeling.

Nonstandard Abbreviations and Acronyms

AAA

aortic aneurysm

AKR1C3

aldo-keto reductase family 1 member C3

Ang

angiotensin

ANP

atrial natriuretic peptide

AA

arachidonic acid

BP

blood pressure

CM-Cox-2 KO

cardiomyocyte-specific deletion of Cox-2

COX

cyclooxygenase

cPGES

cytosolic PGE2 synthase

CRTH2

chemoattractant receptor-homologous molecule

CV

cardiovascular

CVD

cardiovascular disease

DPr

prostaglandin D receptor

EC

endothelial cell

EF

ejection fraction

EPr

prostaglandin E receptor

FPr

prostaglandin F receptor

GWAS

genome-wide association study

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HFD

high fat diet

H-PGDS

hematopoietic prostaglandin D2 synthase

HSD

high salt diet

HTN

hypertension

IPr

prostacyclin receptor

I/R

ischemia reperfusion

KO

knockout

L-PGDS

lipocalin prostaglandin D synthase

MI

myocardial infarction

MMP

metalloprotease

mPGES

microsomal prostaglandin E2 synthase

NO

nitric oxide

NSAID

non-steroidal anti-inflammatory drugs

PG

prostaglandin

PGFS

prostaglandin F2 synthase

PGI2

prostacyclin

PGIS

prostacyclin synthase

SNP

single nucleotide polymorphism

TBXS

thromboxane synthase

TPr

thromboxane receptor

Tx

thromboxane

VSMC

vascular smooth muscle cell