LncRNA H19: A Novel Biomarker in Cardiovascular Disease

Abstract

Cardiovascular disease is a major cause of death and disability worldwide. Recently, increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the pathogenesis of cardiovascular diseases, including atherosclerosis, coronary artery disease, dilated cardiomyopathy, diabetic cardiomyopathy, aortic dissection, and more. LncRNA H19 was the first to be described as a non-protein-coding mRNA-like molecule. A large number of studies have found that lncRNA H19 is related to the pathophysiological processes of cardiovascular diseases, and it is emerging as a potential key regulator of various heart diseases. In this review, we aim to summarize the role of lncRNA H19 in cardiovascular diseases in order to provide a theoretical basis for its potential use as a new therapeutic target in the future.

Abbreviations

AAA, Abdominal aortic aneurysm

AMI, Acute myocardial infarction

AS, Arteriosclerosis

ATG7, Autophagy related protein 7

CAD, Coronary artery disease

cIAP1, Cellular inhibitor of apoptosis protein 1

CTCF, CCCTC binding factor

CTGF, Connective tissue growth factor

CYP1B1, Cytochrome P450 1B1

DIRAS3, Distinct subgroup of the Ras family member 3

DUSP5, Dual specificity phosphatase 5

EBP1, Eukaryotic translation initiation factor 4E binding protein 1

EIF4, Eukaryotic translation initiation factor 4

ERK1/2, Extracellular signal regulated kinase 1/2

FGF-21, Fibroblast growth factor 21

HaoEC, Human aortic endothelial cells

HA-VSMCs, Human aortic vascular smooth muscle cells

HF, Heart failure

HL-1, A cardiac muscle cell line

HUVEC, Human umbilical vein endothelial

I/R, Ischemia reperfusion

IGF, Insulin-like growth factor

lncRNA, Long non coding RNA

MI, Miocardial infarction

miR, Micro RNA

mTORC1, Mammalian target of rapamycin complex 1

nc-RNA, Non-coding RNA

NF-κB, Nuclear factor kappa-B

PA, Pulmonary arteries

PAH, Pulmonary artery hypertension

PBX3, Pre-leukemia transcription factor 3

PDK1, 3-phosphoinositide-dependent protein kinase 1

PPARα, Peroxisome proliferators-activated receptor α

Pro, Promote

STAT3, Signal transducer and activator of transcription 3

TET1, Ten-eleven translocation 1

TGF-β, Transforming growth factor β

VDAC1, Voltage dependent anion channel

VSMC, Vascular smooth muscle cell

WNT1, Wingless MMTV integration sit

WCH, White coat hypertension

INTRODUCTION

Despite improvements in interventional and pharmacological therapies, cardiovascular disease remains the leading cause of hospitalization and mortality worldwide. The pathogenesis of many cardiovascular diseases remains unclear, which is a matter of intense research. Non-coding RNA (nc-RNA) H19 is one of the lncRNAs, which are ≥ 200 nucleotides in length. It has a total length of 2.5 kb, including 5 exons and 4 introns, and is transcribed from the H19/IGF2 gene located on human chromosome 11p15.5. H19 was nominated by Pachnis in 1984 and identified as an abundant fetal transcript in mice.¹ Importantly, lncRNA H19 is well conserved among species,² highly expressed during embryonic development and suppressed in most adult tissues, with a few exceptions such as skeletal muscles and heart.³ In vascular cells, H19 has been identified as a regulator of endothelial cellular aging.⁴ However, in the heart, lncRNA H19 is associated with myocardial hypertrophy.⁵ Available data indicate that lncRNA H19 is involved in a variety of different mechanisms related to development and genetic regulation of cellular homeostasis (Table 1). Accumulating data indicate that the re-expression of lncRNA H19 plays important roles in cardiovascular diseases.^6,7 It is highly expressed in neointima following injuries and human atherosclerotic lesions. This expression may imply that the vascular response to injury is associated with the re-expression of several fetal gene networks.^8,9 Additionally, H19 has been demonstrated to exacerbate cardiac hypertrophy⁵ and atherosclerosis,¹⁰ and it is known to be involved in physiological and pathological conditions with regulatory and structural roles in numerous biological processes, including cell proliferation, pyroptosis, autophagy, and apoptosis. In this review, we discuss specific studies that have provided insights into the function of lncRNA H19 in cardiovascular diseases (Figure 1).

Table 1. Impact of lncRNA H19 in cardiovascular diseases.

Model	Cellular behaviour	List of known regulator/binding partner	Related function	Brief role in disease	Ref.
Patients, HUVEC	Proliferation, apoptosis	NF-κB	Promote proliferation, Inhibit apoptosis	Promote AS	12
Mouse	-	CTCF/PDK1	Promote plaque formation, intraplaque angiogenesis	Promote AS	15
Patients, Raw264.7 cells	Adipogenesis and in-flammation response	miR-130b	Lipid accumulation and inflammation response	Promote AS	16
Patients, HA-VSMCs	Apoptosis	miR-148b, WNT1	Promote proliferation and suppress apoptosis	Promote AS	17
Patients, Mouse	Proliferation, senescence	STAT3	Anti-aging	Inhibit AS	4
Mouse, Human VSMCs	Autophagy	DUSP5	Anti-autophagy	Inhibit AS	18
Patients	-	lncRNA MALAT1	-	Promote hypertension	10
Patients	-	TGF-β	-	Promote CAD	10
Patients	-	lncRNA LIPCAR	-	Promote CAD	27
HUVEC, HaoEC, Mouse	-	TET1, TGF-β1	-	Promote CAD	25, 28
Mouse	Pyroptosis	PBX3/CYP1B1	Anti-pyroptosis	Inhibit MI	31
Mouse	Apoptosis	miR-29b	Anti-apoptosis	Inhibit MI	32
Patients	-	lncRNA MIAT, lncRNA MALAT1	-	Promote MI	36
Mouse	Apoptosis	miR-675/PPARα	Pro-apoptosis	Promote I/R injury	38
Mouse	Apoptosis	miR-22-3p	Anti-apoptosis	Inhibit I/R injury	40
Mouse H9C2 cells	-	miR-29b-3p/cIAP1	Anti-apoptosis/promote methylation	Inhibit I/R injury	37, 41
Mouse HL-1	Autophagy	miR-143/ATG7	Anti-apoptosis	Inhibit I/R injury	43
Mouse	Apoptosis	miR-29b-3p/cIAPI, miR-1	Anti-fibrosis	Inhibit I/R injury	41, 45
Patients, Mouse	Flammation response	IL-6, MCP-1	Promote flammation	Promote AAA	43
Patients, Mouse	-	miR-193b-3p	-	Promote aortic dissection	48
Mouse	Proliferation	mTORC1/EIF4, EBP1, FGF21	Anti-proliferation	Inhibit PH	50
Rats	Proliferation	LncRNAMIAT, miR29a, miR33a	Anti-proliferation	Inhibit PH	51
Mouse	Autophagy	DIRAS3	Anti-autophagy	Inhibit HF	53
Mouse	-	miR-675	-	Promote HF	5
Mouse, Cell	-	DUSP5/ERK1/2	-	Promote HF	54
Mouse	Fibrosis	miR-455	Promote fibrosis	Promote HF	56
Mouse	Apoptosis	miR-675/VDAC1	Anti-apoptosis	Inhibit HF	57

AAA, abdominal aortic aneurysm; ACP5, acid phosphatase 5; ALKBH5, alkB, alkylation repair homolog 5; AS, arteriosclerosis; ATG7, autophagy related protein 7; BCL-2, B-cell lymphoma/Leukemia-2; CAD, coronary artery disease; cIAPI, cellular inhibitor of apoptosis protein 1; CTCF, CCCTC binding factor; CYP1B1, cytochrome P450 1B1; DIRAS3, distinct subgroup of the Ras family member 3; DUSP5, dual specificity phosphatase 5; EBP1, eukaryotic translation initiation factor 4E binding protein 1; EIF4, eukaryotic translation initiation factor 4; FGF21, fibroblast growth factor 21; HF, heart failure; HL-1, a cardiac muscle cell line; IL-6, interleukin-6; lncRNA, long non coding RNA; I/R, ischemia reperfusion; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattratctant protein-1; MI, miocardial infarction; miR, micro RNA; mTORC1, Mammalian target of rapamycin complex 1; NF-κB, nuclear factor kappa-B; PBX3, pre-leukemia transcription factor 3; PDK1, 3-phosphoinositide-dependent protein kinase 1; PH, pulmonary hypertension; PPARα, peroxisome proliferators-activated receptor α; STAT3, signal transducer and activator of transcription 3; TET1, ten-eleven translocation 1; TGF-β, transforming growth factor β; VDAC1, voltage dependent anion channel; WNT1, wingless MMTV integration sit.

Figure 1.

Localization and function of long non coding RNA. LncRNA is located in the nucleus and cytoplasm, and can be released outside the cell with the action mechanism of lncRNA as shown in the figure: 1. Binding to the upstream promoter region of the protein coding gene and interferes with the downstream gene expression. 2. Inhibit RNA polymerase and regulate downstream gene expression. 3. Mediates chromatin remodeling and histone modification and affects downstream gene expression. 4. Form complementary double strands with the transcripts of protein coding genes, interfering with mRNA splicing and forming endogenous siRNA. 5. Binding with specific proteins to regulate the activity of target proteins. 6. Forming nucleic acid protein complexes as structural components. 7. Binding to a specific protein, changing the cellular location of the protein. 8. Acting as precursor molecules of small molecules. 9. Phosphorylate specific proteins. 10. Some lncRNAs are released in exosomes or microvesicles, potentially facilitating cell-to-cell communication.

ROLE OF lncRNA H19 IN CARDIOVASCULAR DISEASES

Atherosclerosis

Atherogenesis (AS) is a slowly progressive process characterized by multifocal structural alterations in the walls of large and medium-sized arteries, leading to the formation of atherosclerotic plaques. Atherosclerosis is a multistep cardiovascular disease promoted by several risk factors. Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. LncRNAs have been proven to play important roles in the biological and pathological processes of atherosclerosis. LncRNA H19 is highly expressed in atherosclerosis tissue. It can act on target miRNA or target proteins, activate inflammatory pathways, inhibit the apoptosis of vascular smooth muscle cells (VSMCs), promote angiogenesis in plaque, and accelerate the occurrence and development of atherosclerosis lesions, making it a potential therapeutic target.¹¹ LncRNA H19 has been reported to promote the proliferation of vascular endothelial cells in arteriosclerosis obliterans and inhibit their apoptosis via the nuclear factor kappa-B (NF-κB) pathway.¹² Previous trials have found that lncRNA H19 is highly expressed in human atherosclerotic plaques and injured carotid arteries in rats but barely expressed in normal coronary arteries.¹³ Recent studies have shown that an increased plasma level of lncRNA H19 is associated with an increased risk of coronary artery disease.¹⁰ In patients with atherosclerosis, a high level of lncRNA H19 has been detected in plaque, and the upregulation of lncRNA H19 has been shown to promote the proliferation and inhibit the apoptosis of VSMCs.¹⁰ Increased H19 expression has been shown to accelerate atherosclerosis by activating inflammatory pathways, while H19 silencing has been shown to suppress ex vivo adipogenesis and inflammatory responses induced by oxidized low-density lipoprotein (ox-LDL) treatment.¹¹ Furthermore, Huang et al. reported that the upregulation of lncRNA H19 contributes to the occurrence of atherosclerosis.¹⁴ Studies provide evidence that H19 recruits CCCTC binding factor (CTCF) to downregulate the expression of 3-phosphoinositide-dependent protein kinase 1 (PKD1), thereby promoting vulnerable plaque formation and intraplaque angiogenesis in mice with atherosclerosis.¹⁵ In a study using short hairpin RNA in ox-LDL-treated Raw 264.7 cells, Han demonstrated that miR-130b is an important target gene of lncRNA H19. This axis could regulate inflammation responses and lipid metabolism, serving as a potential target for treating AS.¹⁶ Another experiment conducted by Zhang indicated that lncRNA H19 acts as a competing endogenous RNA (ceRNA) of miR-148b, thereby modulating the WNT/β-catenin signaling pathway to promote the proliferation and suppress the apoptosis of ox-LDL-stimulated VSMCs.¹⁷ The lncRNAs HOTAIR and H19 have also been shown to play important roles in endothelial cell senescence; H19 limits endothelial inflammation and senescence by inhibiting the STAT3 signaling pathway.⁴ Another study demonstrated that Astragaloside IV could attenuate the autophagy and mineralization of VSMCs in atherosclerosis, and that this may be associated with H19 upregulation and inhibition of dual specificity phosphatase 5 (DUSP5).¹⁸ In short, lncRNA H19 can regulate changes of atherosclerotic plaque by modulating target cell effector genes and proteins, making it an effective marker for evaluating the condition.

Hypertension

Hypertension is a common chronic disease and one of the major risk factors for cardiovascular disease worldwide. The prevalence of hypertension has increased in the past several decades.¹⁹ Hypertension is influenced by multiple environmental and genetic determinants and is characterized by impaired vascular endothelial function.²⁰ The significance of lncRNAs is being increasingly recognized in hypertension, but it remains largely unexplored.²¹ Research has suggested that the expressions of circulating lncRNA H19 and lncRNA MALAT1 are negatively associated with ambulatory blood pressure monitoring, while no rectilinear correlation has been found between their expression levels and clinical blood pressure.^22,23 In addition, significantly increased expression levels of lncRNA H19 and lncRNA MALAT1 have been reported in subjects with white coat hypertension (WCH). Based on analysis of the key pathogenesis of WCH, it has been hypothesized that lncRNA H19 may activate the sympathetic nervous system, however this hypothesis requires further verification.

Coronary artery disease

Coronary artery disease (CAD) is the leading type of heart disease, developing when major blood vessels responsible for supplying oxygen, blood, and nutrients to the heart become diseased or damaged due to the formation of plaques.²⁴ A recent study showed a significant correlation between lncRNA H19 and an increased risk of CAD. In addition, the serum level of lncRNA H19 has been reported to be higher in patients with CAD compared to healthy individuals or patients with other types of cardiovascular diseases.²⁵ Research suggests that lncRNA H19 activates oxidative stress and inflammatory response pathways, leading to endothelial damage, which is the fundamental mechanism of coronary heart disease. Serum lncRNA H19 can serve as a stable, specific and accurate diagnostic marker for CAD. Its expression level has been positively correlated with the plasma level of transforming growth factor-β1 (TGF-β1), and the upregulation of lncRNA H19 has been shown to significantly increase the TGF-β1 protein level in human coronary artery endothelial cells.²⁵ Similarly, another study¹⁰ indicated the upregulation of lncRNA H19 in CAD patients compared to controls, suggesting its involvement in CAD progression. Huang et al.²⁶ also suggested that lncRNA H19 has the potential to be a diagnostic biomarker for CAD. They found that the rs4929984 polymorphism is associated with susceptibility of females to CAD in the Han Chinese population, and that lncRNA H19 variants are capable of influencing lipid metabolism, inflammation, and coagulation function in CAD patients. Furthermore, another study showed that the plasma levels of two lncRNAs, H19 and LIPCAR were significantly increased in patients with CAD and independently acted as risk factors for CAD.²⁷ Additionally, a recent study reported abnormal expressions of lncRNA H19 and ten-eleven translocation 1 (TET1) in endothelial cells of human atherosclerotic coronary arteries. Endothelial activation of the H19/TET1 axis may play an important role in endothelial-to-mesenchymal transition (EndMT) and possibly CVD.²⁸ The results of this study indicated a close relationship between lncRNA H19 and injury of vascular endothelial cells, ultimately promoting atherosclerosis by activating other signal transduction pathways.

Myocardial infarction

Myocardial infarction (MI) is a well-known consequence of myocardial necrosis and myocardial ischemia resulting from atherothrombosis.^29,30 Recently, several studies have shown that lncRNA H19 has a protective role in cardiomyocytes during the MI process. One study demonstrated the downregulation of H19 expression in MI patients. To further explore the underlying mechanism, an MI rat model and cardiomyocytes were used to investigate the gain and loss function of H19/CYP1B1, and the results showed that lncRNA H19 could suppress the pyroptosis of cardiomyocytes to attenuate MI progression by regulating the PBX3/CYP1B1 axis.³¹ Another study indicated that lncRNA H19 protects cardiomyocytes against acute myocardial infarction (AMI) via anti-apoptosis by targeting miR-29b.³² Moreover H19 was significantly downregulated after MI. LncRNA H19 ameliorates MI-induced myocardial injury and maladaptive cardiac remodeling by regulating KDM3A. Functionally, another study showed that enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation.³³ However, H19 knockdown resulted in the opposite effects. In contrast, lncRNA H19 was shown to be significantly upregulated in the infarct area post-surgery day 4 in a mouse model.³⁴ The ectopic expression of H19 in mouse hearts resulted in severe cardiac dilation and fibrosis. Furthermore, the expression level of H19 in plasma can be considered as a biomarker of myocardial infarction.³⁵ Wang et al.³⁶ conducted research that demonstrated that three of 10 studied lncRNAs, namely H19, MIAT and MALAT1 were markedly increased in AMI participants compared to healthy volunteers, indicating that these three lncRNAs may be promising diagnostic biomarkers for AMI.

Myocardial ischemic-reperfusion injury

Ischemic cardiomyocyte reperfusion can induce additional cell death and increase infarct size, a phenomenon known as myocardial ischemia-reperfusion (I/R) injury, for which there is still no effective therapy.³⁷ Increasing evidence has indicated that lncRNAs and miRNAs play important roles in the pathogenesis of myocardial I/R injury. Several studies have shown that lncRNA H19 has regulatory effects on multiple pathways involved in energy metabolism, oxidative stress, and inflammation regulation, ultimately exerting a protective effect on myocardial I/R injury. The inhibition of lncRNA H19 has been shown to protect the heart against myocardial I/R injury, which may be partly attributed to the regulation of the miR-675/PPARα axis.³⁸ LncRNA H19 is involved in myocardial ischemic preconditioning by increasing the stability of nucleolin protein, and lncRNA H19 may represent a potential therapeutic target for the treatment of myocardial injury.³⁹ Furthermore, lncRNA H19 has been shown to mediate cardioprotective efficiency by targeting miR-22-3P during myocardial ischemia-reperfusion injury.⁴⁰ Another study showed that dexmedetomidine plays a protective role against I/R-induced injury of aged myocardial cells through ALKBH5/H19/miR-29b-3p/cIAP.⁴¹ LncRNA H19 has also been shown to alleviate cardiomyocyte apoptosis and myocardial I/R injury by suppressing the miR-877-3p-Bcl-2-mediated mitochondrial apoptotic pathway.⁴² In addition, pretreatment with 6-Gingerol has been shown to alleviate I/R-induced myocardial injury both in vitro and in vivo by upregulating H19 expression, which in turn promotes the cellular autophagy pathway by sequestering miR-143 from ATG7 3′UTR.⁴³ Zhang et al.⁴⁴ suggested that H19 mediates the anti-apoptotic effect of H/Post against I/R-induced injury to aged cardiomyocytes by inhibiting miR-29b-3p expression. Meanwhile, lncRNA H19 may improve MI injury by downregulating the expression of miRNA-1 directly.⁴⁵ In conclusion, lncRNA H19 can affect the pathophysiological process of I/R injury by regulating the expression of many miRNAs or mRNAs, and this is expected to become a new diagnostic and therapeutic target in clinical practice.

Aortic aneurysm and aortic dissection

Acute aortic dissection and aortic aneurysm is a life-threatening medical emergency associated with high rates of morbidity and mortality. Abdominal aortic aneurysm (AAA) is an aberrantly enlarged aorta that is generally asymptomatic, and rupture is often unexpected and highly lethal. AAA is considered a chronic vascular inflammatory disease and is characterized by monocyte/macrophage cell infiltration into the aortic layers, accompanied by excessive proinflammatory molecules and chemokines. Emerging evidence has proposed that lncRNA H19 is a crucial mediator in promoting inflammation and vascular damage. Sun showed that H19 was re-expressed in Ang II-induced adult mouse aortic aneurysms.⁴⁶ H19 upregulation promoted AAA formation by enhancing vascular proinflammatory interleukin 6 and monocyte chemoattractant protein-1 and enhancing macrophage infiltration, while H19 deficiency reduced AAA formation by alleviating the expressions of these molecules after Ang II infusion. Moreover, aortic H19 upregulation was shown to be induced by hyperhomocysteinemia, a non-homeostatic state strongly associated with AAA formation and the exacerbation of inflammation and atherosclerosis in ApoE-/- mice.⁴⁷ Meanwhile, the expression level of lncRNA H19 has been shown to be upregulated and the expression of miR-193b-3p downregulated in patients with Alzheimer’s disease and mouse thoracic aorta tissues.⁴⁸ LncRNA H19 regulated smooth muscle cell func-tion by sponging miR-193b-3p and participating in the development of aortic dissection. The expression and regulation of lncRNA H19 in aortic aneurysm and aortic dissection is of great practical significance, and may aid in the early assessment and prevention of sudden rupture.

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by vasoconstriction and progressive obliteration of distal pulmonary arteries (PA) leading to the elevation of PA pressure and right ventricular failure.⁴⁹ LncRNA H19 has been shown to be upregulated in decompensated right ventricles from PAH patients and to be correlated with right ventricular hypertrophy and fibrosis.²³ It has been suggested that lncRNA H19 mediates vascular endothelial injury and vascular smooth muscle remodeling, and that this may serve as a new therapeutic target to impede the development of maladaptive right ventricular remodeling and a promising biomarker of PAH severity and prognosis. Research by Li et al.⁵⁰ suggested that gain and loss of function assays demonstrated that fibroblast growth factor 21 (FGF-21) suppressed the hypoxia-induced proliferation of pulmonary artery smooth muscle cells partially through the upregulation of lncRNA H19. This work highlights the important role of lncRNA H19 in PAH treated with FGF-21, and suggests a mechanism involving mTORC1/EIF4EBP1 inhibition. Another study indicated that the beneficial effects of perillyl alcohol and quercetin on PAH-induced abnormalities were exerted through restoring the dysregulated expression of lncRNA H19, lncRNA MIAT, miR-29a, and miR-33a to normal levels in rats with monocrotaline-induced PAH.⁵¹ LncRNA H19 regulates the occurrence and development of pulmonary hypertension through different targets, providing a new target for the clinical diagnosis, treatment and evaluation of the disease.

Heart failure

Heart failure (HF) is estimated to be the cardiovascular disease with the worst rates of morbidity and mortality, accounting for one of the highest healthcare costs worldwide. The 1-year survival rate of patients with end-stage HF is approximately 50%.⁵² Research suggests that serum lncRNA H19 is upregulated in patients with HF and that it acts as a regulator promoting myocardial fibrosis. LncRNA H19 has been shown to inhibit autophagy in cardiomyocytes by epigenetically silencing DIRAS3, providing novel insights into understanding the molecular mechanisms of diabetic cardiomyopathy.⁵³ Liu et al.⁵ first detected the expression of H19 and its encoded miR-675 in both normal and diseased hearts, verifying their upregulation in pathological cardiac hypertrophy and HF. Additionally, lncRNA H19 has been shown to contribute to cardiac fibroblast proliferation and fibrosis, partly through the repression of DUSP5/ERK1/2.⁵⁴ Furthermore, H19 has been shown to be highly conserved and downregulated in failing hearts from mice, pigs and humans, and H19 gene therapy has been shown to prevent and reverse experimental pressure-overload-induced HF. H19 has been shown to act as an anti-hypertrophic lncRNA and to represent a promising therapeutic target to combat pathological cardiac remodeling.⁵⁵ In addition, lncRNA H19 knockdown has been shown to enhance the antifibrotic role of miR-455 and attenuate connective tissue growth factor (CTGF) expression and further decrease cardiac fibrosis-associated protein synthesis such as collagen I, III and α-SMA. This suggests the potential therapeutic role of H19 in cardiac diseases.⁵⁶ H19 has recently been identified as an important regulator of T1DM cardiomyopathy in experimental rats. Sprague-Dawley rats injected with streptozotocin developed T1DM cardiomyopathy with a decreased expression of cardiac H19, and the upregulation of H19 in myocardial tissues caused decreases in oxidative stress, inflammation, apoptosis, and autophagy, leading to the amelioration of diabetes cardiomyopathy (DCM).^53,57 Huang et al.⁵⁶ revealed the crucial regulation of lncRNA H19 in fibrogenesis in diabetic cardiac fibro-blasts through binding miR-455 targeting CTGF, suggesting the role of the lncRNA/miRNA/mRNA regulation pathway in cardiac fibrosis. Further research data revealed a novel function of the H19/miR-675/VDAC1 pathway in the regulation of high glucose-mediated apoptosis, providing valuable insights for understanding the pathogenic role of lncRNA H19 in the development of DCM.⁵⁷ These experiments suggest that lncRNA H19 is involved in the different pathological processes of HF through different molecular mechanisms, and this may establish a solid foundation for the future development of novel treatments for HF (Figure 2).

Figure 2.

The role of LncRNA H19 in cardiovascular disease. Schematic diagram of some of the different cardiovascular disease pathways that lncRNA H19 influences, including hypertension, coronary artery disease, myocardial infarction, myocardial ischemic-reperfusion injury, atherosclerosis, aortic aneurysm and aortic dissection, pulmonary hypertension and heart failure, involving pathophysiological processes such as inflammation, apoptosis, pyroptosis, fibrosis et al. Among the reported role of lncRNA H19 can promote the occurrence and development of disease, while some do opposite. Additionally, miRNA plays a key role in regulation of pathophysiological processes. AAA, abdominal aortic aneurysm; ACP5, acid phosphatase 5; ALKBH5, alkB, alkylation repair homolog 5; AS, arteriosclerosis; BCL-2, B-cell lymphoma/Leukemia-2; CAD, coronary artery disease; CTCF, CCCTC binding factor; CTGF, connective tissue growth factor; CYP1B1, cytochrome P450 1B1; DIRAS3, distinct subgroup of the Ras family member 3; DUSP5, dual specificity phosphatase 5; ERK1/2, extracellular signal regulated kinase 1/2; FGF21, fibroblast growth factor 21; IL-6, interleukin-6; I/R, ischemia reperfusion; lncRNA, long non coding RNA; MAPK, mitogen-activated protein kinase; MI, miocardial infarction; miR, micro RNA; mTORC1, Mammalian target of rapamycin complex 1; NF-κB, Nuclear factor kappa-B; PBX3, pre-leukemia transcription factor 3; PDK1, 3-phosphoinositide-dependent protein kinase 1; PH, pulmonary hypertension; PPARα, peroxisome proliferators-activated receptor α; TET1, ten-eleven translocation 1; TGF-β, transforming growth factor β; VDAC1, voltage dependent anion channel; WCH, white coat hypertension; WNT1, wingless MMTV integration sit.

CONCLUSIONS

Cardiovascular disease is a serious public health problem due to its high morbidity and mortality. Consequently, it is urgent to develop more biomarkers with high sensitivity and specificity for the diagnosis and treatment of the disease. In recent years, ncRNAs have garnered significant attention from researchers and have shown unique advantages in cardiovascular diseases. Similarly, the role of lncRNA H19 in the diagnosis, treatment, and prognosis of cardiovascular diseases has received considerable attention. An increasing number of studies have indicated that lncRNA H19 may play a significant role in heart diseases through its aberrant expression and its association with the development and progression of cardiovascular diseases. In this review, we focused on the role of lncRNA H19 in hypertension, coronary artery disease, myocardial infarction, myocardial ischemic-reperfusion injury, atherosclerosis, aortic aneurysm and aortic dissection, pulmonary hypertension and heart failure. We discussed the physiological and pathological regulatory functions of lncRNA H19 in these cardiovascular diseases. The involvement of lncRNA H19 in cardiovascular diseases opens up new possibilities for evaluating molecular markers for the disease, offering novel alternative targets for better diagnosis and therapy in the future. Considering the complexity of the regulatory mechanisms, which involve a wide range of crosstalk, many mechanisms are still unclear and require further exploration.

DECLARATION OF CONFLICT OF INTEREST

All the authors declare no conflict of interest.