Alpha-7 nicotinic acetylcholine receptor: targeting the interplay between inflammation, renin-angiotensin aldosterone system, and nervous system for the novel treatment of heart failure

Abstract

The incidence and prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) continue to rise, yet evidence-based therapy remains limited. Due to the complexity of HFpEF pathology, traditional HF medication has shown inconsistent efficacy in improving clinical outcomes and reducing morbidity. Therefore, highlighting the urgent need for novel interventions. The αlpha-7 nicotinic acetylcholine receptor (α7nAChR) is a central mediator of the cholinergic anti-inflammatory pathway and has emerged as a promising therapeutic target in various conditions, such as sepsis, arthritis, metabolic dysfunction, and atherosclerosis. This review aims to examine the emerging therapeutic potential of α7nAChR in HF and HFpEF pathology, focusing on its protective role in modulating the complex interplay between systemic and cardiovascular inflammation, renin-angiotensin-aldosterone system activation, neurocardiac signaling and metabolic dysfunction.

1. Introduction

Cardiovascular diseases (CVDs) comprise a broad range of disorders affecting the heart and blood vessels, including atherosclerosis, coronary artery disease, myocardial infarction, hypertension, and heart failure (HF) (Roth et al., 2020). Among these, HF is a leading cause of morbidity and mortality, affecting over 64 million people worldwide (Norhammar et al., 2023; Savarese et al., 2022). In western populations, HF prevalence rises from approximately 1% in individuals under 55 years to 10% in those over 70 years (McDonagh et al., 2021). The European Society of Cardiology categorizes HF based on left ventricle ejection fraction (LVEF) into three groups: HF with preserved (HFpEF; LVEF ≥50%), reduced (HFrEF; LVEF <40%), and mildly reduced ejection fraction (HFmrEF; LVEF 40%–49%) (McDonagh et al., 2021). These guidelines are used to assist healthcare professionals in diagnosing, managing symptoms (Figure 1), and selecting treatment strategies for patients suffering from acute and chronic HF.

FIGURE 1.

Conceptual schematic of common signs and symptoms of left- and right-sided HF. HF arises from structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures, weakening of the heart muscle, and/or inadequate cardiac output that occur at rest and/or during physical activity (McDonagh et al., 2021). Non-invasive physical examination remains important in managing HF, and patients presenting with left- or right-sided HF display distinct signs and symptoms that may aid in the diagnosis and treatment strategy (Dini et al., 2023; Thibodeau and Drazner, 2018). Image created with BioRender.com.

HFpEF is characterized by impaired diastolic relaxation and elevated pressure despite preserving systolic function (Naing et al., 2019). HFpEF accounts for approximately 50% of HF cases, with its prevalence rising significantly over the past few decades (Vasan et al., 2018). Currently, there is a lack of evidence-based interventions for HFpEF, partly due to its heterogeneous nature, which makes the condition difficult to target and effectively manage. Underlying aetiologias are driven by various modifiable and non-modifiable factors, as summarized in Figure 2, and include age (Tromp et al., 2021), sex (Lala et al., 2022), genetics (Lee DS. et al., 2025), obesity (Rayner et al., 2025), diabetes, and pre-existing cardiovascular conditions (Brar et al., 2025; Bahit et al., 2018; Samsky et al., 2021). While many pre-existing cardiovascular conditions are associated with HF, hypertension remains the highest risk factor for HFpEF, particularly in the elderly. Despite therapeutic advances, the overall 5-year survival rate of HF is approximately 50% (Zhou et al., 2024; Khan et al., 2024). Thus, it stands to reason that treatments targeting the underlying risk factors and conditions may help stem the growing global burden of HF. While the use of renin-angiotensin-aldosterone system (RAAS) inhibitors, beta blockers, and mineralocorticoid (aldosterone) receptor antagonists are mainstays in the treatment of HF (McDonagh et al., 2021), these anti-hypertensive agents have failed to show consistent prognostic improvements in HFpEF (Rist et al., 2024; Beldhuis et al., 2017; Odajima et al., 2022; Conraads et al., 2012; Pitt et al., 2014; Solomon et al., 2019; Yamamo et al., 2013). Therefore, there is undoubtedly an urgent need for additional effective therapeutic strategies.

FIGURE 2.

Non-modifiable and modifiable risk factors correlated with HF. Non-modifiable risk factors are characteristics that are unable to be altered and influence an individual’s likelihood of developing HF, and include age (Tromp et al., 2021), ethnicity (Savitz et al., 2021), family history (Rasooly et al., 2023), genetic predisposition (Lee DS. et al., 2025), pre-existing cardiovascular incident (e.g., atherosclerosis, coronary artery disease, myocardial infarction, and peripheral artery disease) (Brar et al., 2025; Samsky et al., 2021) and sex (Lala et al., 2022). Conversely, modifiable risk factors are behaviors and traits that can be changed and controlled, and impact an individual’s probability of developing HF, including alcohol consumption (Lee D-I. et al., 2025), dyslipidemia (Nebuwa et al., 2024), hyperglycemia (Chioncel and Ambrosy, 2020), hyperhomocysteinemia (HHcy) (Karger et al., 2025), hypertension (Baffour et al., 2024), obesity (Rayner et al., 2025), poor diet (Billingsley et al., 2020) physical inactivity (Aune et al., 2021), smoking (Watson et al., 2019) and type II diabetes mellitus (Kenny and Abel, 2019). Image created with BioRender.com.

The alpha-7 nicotinic acetylcholine (ACh) receptor (α7nAChR) is a key protein of the cholinergic anti-inflammatory pathway, which links the nervous and inflammatory systems (Noviello et al., 2021). This pathway has gained significant attention for its therapeutic potential in several inflammatory conditions, including atherosclerosis (Vieira-Alves et al., 2020), cancer (Arunrungvichian et al., 2023), neurodegenerative disorders (Let et al., 2022; Yang et al., 2017), and rheumatoid arthritis (Wu et al., 2025). HF with HFpEF is increasingly recognized as the result of a complex interplay between low-grade systemic inflammation, RAAS activation, microvascular injury, metabolic dysregulation, and neural dysfunction (Hartupee and Mann, 2017). These processes promote myocardial damage through pathological cardiac remodeling (i.e., ventricular wall thickening and fibrosis), inflammation, oxidative stress, and increased myocyte apoptosis (Hartupee and Mann, 2017).

Given that interconnected pathways are increasingly explored for novel treatments (Bauersachs et al., 2025), this review seeks to examine the emerging role of α7nAChR in the interplay between anti-inflammatory signaling, the RAAS, and neurocardiac and metabolic regulation to determine its therapeutic potential for HF and HFpEF. To our knowledge, this is the first review to consolidate experimental and clinical evidence, directly linking α7nAChR signaling to HF pathology, with an emphasis on HFpEF. Relevant peer-reviewed publications focusing on α7nAChR signaling in CVDs, HF, and associated pathology were used.

2. Physiology of α7nAChR

The ACh receptor (AChR) is a well-characterized cholinergic membrane receptor that mediates the physiological responses of ACh across neuronal and non-neuronal pathways (Reichrath et al., 2016; Saw et al., 2021; Wessler and Kirkpatrick, 2008). AChRs are broadly classified into two types: (i) muscarinic AChRs, which are primarily involved in parasympathetic nervous system signaling, and (ii) nicotinic AChR (nAChR), a family of ligand-gated ion channels comprising 17 different subunits (ɑ1-ɑ10, β1-β4, γ, δ, and ε), each contributing to diverse physiological roles (Xu et al., 2021). Among these, the α7nAChR, encoded by the CHRNA7 gene, is one of the most abundantly expressed subtypes (Xu et al., 2021). Initially identified in the central nervous system, ɑ7nAChRs were observed to play an important role in mediating fast synaptic transmissions, neurotransmitter release, and ion influx to regulate cognitive processes (Barrantes et al., 1994; Rathouz and Berg, 1994). Compared to other nAChR subtypes, ɑ7nAChR displays unique characteristics, including high Ca²⁺ permeability and rapid activation-desensitization kinetics (Xu et al., 2021). The receptor exists in three functional states: resting (closed), active (open), and desensitized (closed) (Noviello et al., 2021). Beyond its role in neurons, more recently, ɑ7nAChR expression has also been documented on a variety of non-neuronal cells, including hepatocytes (Li et al., 2019), cardiomyocytes (Vang et al., 2021; Broide et al., 2019), cardiac fibroblasts (Li et al., 2019), endothelial cells (Li et al., 2019; Broide et al., 2019), vascular smooth cells (Li et al., 2019; Wada et al., 2007), stromal cells and immune cells (e.g., leukocytes, macrophages, dendritic cells, T-cells, and B-cells) (Schloss et al., 2022; Keever et al., 2024; Mashimo et al., 2019), where it plays a critical role in physiological homeostasis.

2.1. Activation and inhibition of α7nAChR

Despite its therapeutic potential, direct activation of ɑ7nAChR using endogenous agonists, such as ACh and nicotine, remains challenging. Nicotine is a non-selective agonist of nAChR subtypes, with known toxicity and addictive properties that restrict its clinical use (Cao et al., 2024). Meanwhile, ACh, is rapidly degraded by cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and lacks receptor specificity (Liu et al., 2024). Early pharmacological efforts focused on orthostatic ligands, compounds that bind to the orthostatic site within the receptor and induce partial or full agonism, mimicking ACh by inducing ion channel opening, as well as competitive antagonists, which block receptor activity (Yang et al., 2017; Manetti et al., 2023) (Table 1). More recently, a significant advancement in ɑ7nAChR pharmacology is the development of positive allosteric modulators (PAMs). Unlike orthostatic agonists, PAMs bind to distinct allosteric sites on the extracellular domain and enhance the receptor responsiveness to ligands without directly activating the channel (Hurst et al., 2005; Papke and Horenstein, 2021). PAMs, such as PNU-120596, cannot induce receptor agonism on their own; instead they reduce the refractory period of ɑ7nAChR desensitization to enhance receptor responsiveness in the presence of endogenous or orthostatic agonists (Mueller et al., 2015; Jin et al., 2014). In contrast, PAMs like GAT-107 can activate ɑ7nAChR independently by acting on both the orthostatic and allosteric sites, offering dual-action potential (Bagdas et al., 2016; Gauthier et al., 2021). Although ɑ7nAChR antagonists have limited therapeutic value, they have been instrumental in identifying the biological role of ɑ7nAChR. ɑ-Bungarotoxin (ɑ-BTX), is a neurotoxin derived from the venom of the Many-banded Krait snake (Bungarus multicinctus), which irreversibly blocks ɑ7nAChR, while methyllycaconitine (MLA) is a widely used competitive antagonist known for its specificity in experimental models (Panagis et al., 2000; Prickaerts et al., 2012).

TABLE 1.

Cholinergic agonists and antagonists that target α7nAChR.

Compound	Classification	Chemical structure	Clinical status
ɑ7nAChR agonists
AR-R17779	Selective, full agonist (Fan et al., 2014); may cross react with 5-HT3 receptor (Hammarlund et al., 2021).		N/A
AZ6983	Highly specific; selective over 5-HT3aR and α3β4nAChR (Ulleryd et al., 2019).	Chemical structure undisclosed.	N/A
GAT-107	Strong dual agonist and PAM (Bagdas et al., 2016; Papke et al., 2014).		N/A
GTS-21	Partial and long-lasting agonist; weak α4β2 and 5-HT3 antagonist; also activates α3β4 nAChRs (Yang et al., 2017; Papke and Horenstein, 2021).		Phase I (Obesity) NTC02458313 (2016) Phase I (Inflammation) NCT00783068, 2010 Phase II (Cognition) NCT00414622, 2007
Nicotine	Non-selective agonist; desensitizes with prolonged exposure (Yang et al., 2017; Wittenberg et al., 2020).		​
PHA-543613	Potent and selective agonist; may promote desensitization (Wishka et al., 2006; B et al., 2019).		N/A
PNU-120596	Potent and selective PAM; prevents nicotine-induced desensitization (Kalappa and Uteshev, 2013; Hurst et al., 2005).		N/A
PNU-282987	Potent; selective over α3β4nAChR; rapid desensitization (Bodnar et al., 2005); functional 5-HT3 antagonist (Bodnar et al., 2005).		N/A
BTXɑ7nAChR antagonists
ɑ-BTX	Non-selective for ɑ7 and muscular nAChRs (Noviello et al., 2021); reported as non-competitive; locks binding site inactive (Dacosta et al., 2015).		​
MLA	Highly potent and selective competitive antagonist (Qasem et al., 2023).		​

Abbreviations: α7nAChR, alpha 7 nicotinic acetylcholine receptor; Br, bromide; C, carbon; Cl, chloride; H, hydrogen; N, nitrogen; nAchR, nicotinic acetylcholine receptor; O, oxygen; PAM, positive allosteric modulator; 5-HT₃R, serotonin type-3, receptors.

3. α7nAChR and inflammation

Overwhelming evidence supports that acute and chronic low-grade inflammation plays a central role in the pathogenesis, progression, and severity of HF (Boulet et al., 2024). Systemic and local inflammation have a detrimental effect on myocardial structure and function, with inflammatory mediators enhancing oxidative damage to myocardial cells, fibrosis, ventricular stiffness, and coronary microvascular dysfunction (Bairey Merz et al., 2020; Paulus and Tschope, 2013). Clinical studies report that HFpEF severity is correlated with an elevation in both circulating and cardiac pro-inflammatory cytokines and immune modulators (interleukin (IL)-1β, IL-6, IL-17, tumour necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), nitric oxide (NO), inducible nitric oxide synthase (iNOS), high-mobility group box-1 (HMGB-1) and C-reactive protein) (Chirinos et al., 2020; Delalat et al., 2025; DuBrock et al., 2018; Sanders-van Wijk et al., 2020); infiltration of immune cells [e.g., monocytes, macrophages, and lymphocytes (T and B)] (Kessler et al., 2025; Kneuer et al., 2025; Li et al., 2010); and expression of inflammatory receptors [e.g., pattern recognition receptors (PRR), such as toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE)] (Delalat et al., 2025; Daou et al., 2023). Considering the underlying involvement of inflammation in the pathophysiology of HF, targeting aspects of the immune system has been seen as a viable approach to improving disease severity and patient outcome (Mesquita et al., 2021; Ma et al., 2022; Bashier et al., 2019; Petrie et al., 2018).

Interest in the ɑ7nAChR as a target for suppressing adverse inflammatory responses was first identified in 2003 when it was established that stimulation of the vagus nerve attenuated lipopolysaccharide (LPS)-induced inflammation by inhibiting TNF-ɑ release (Borovikova et al., 2000). Subsequently, a series of α7nACh knockout models confirmed that neuronal and non-neuronal ɑ7nAChR signaling was essential to this anti-inflammatory response and was termed the “cholinergic anti-inflammatory pathway” (Figure 3) (Keever et al., 2024; Wang et al., 2003; Huston et al., 2006; Hoogland et al., 2022; Truong et al., 2015). Originating in the brainstem as a response to afferent vagus nerve stimulation by inflammation, the cholinergic anti-inflammatory pathway consists of neurotransmitter release from the efferent arm of the vagus nerve to the splenic nerve, resulting in noradrenaline (NA) release from splenic cells (Keever et al., 2023). NA binds to adrenergic receptors on the surface of splenic T-cells and B-cells to increase the production of choline acetyltransferase (ChAT), an enzyme responsible for the production and subsequent release of ACh (Keever et al., 2023). ACh then binds to and activates surface ɑ7nAChR on themselves or on macrophages to reduce inflammation by suppressing the release of inflammatory cytokines (i.e., TNF-ɑ, IL-1β, and IL-6), chemokines (i.e., intracellular adhesion molecule-1, vascular cell adhesion-1 and molecule, and MCP-1), and danger associated molecular pattern molecules (DAMPs), such as high-mobility group box-1 (HMGB1) (Mashimo et al., 2019; Keever et al., 2023; Rosas-Ballina et al., 2011; Vieira-Alves et al., 2020; Reardon et al., 2013; Fujii et al., 2017; Zhang W. et al., 2022). Therefore, selective activation of α7nAChR may provide effective inhibition of damaging inflammatory signaling in critical conditions (Table 2).

FIGURE 3.

Schematic diagram of the proposed cholinergic anti-inflammatory pathway. The cholinergic anti-inflammatory pathway stems from activation of efferent vagus nerve (black). This results in the release of ACh within the celiac ganglion to activate sympathetic splenic nerves, triggering the release of noradrenaline (Xie et al., 2020). Noradrenaline then binds to beta-2 adrenergic receptors on T cells resulting in the release of ACh (Xie et al., 2020). ACh activates a7nAChRs located on macrophages and downregulates the release of pro-inflammatory cytokines and immune mediators by inhibiting nuclear activity of NF-κB by immune receptors, such as TLR4 (110) (Simon et al., 2023). Thus, targeting the cholinergic anti-inflammatory pathway is an attractive therapeutic option for the treatment of pathologies, including arthritis (Wu et al., 2025), metabolic dysfunction (Wu YJ. et al., 2021), atherosclerosis (Vieira-Alves et al., 2020) and HF, where chronic inflammation is a hallmark of the disease. Abbreviatiosn: αlpha-7 nicotinic acetylcholine receptor, α7nAChR; ACh, acetylcholine; IL, interleukin; β2AR, beta-2 adrenergic receptor; HMGB1, high-mobility group box-1; NA, noradrenaline; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B-cell; TNF-α, tumor necrosis factor alpha. Image created with BioRender.com.

TABLE 2.

Role of α7nAChR in mitigating inflammation.

Model	Intervention	Outcome	References
In vivo encephalomyelitis-induced inflammation in female C57BL/6 mice	Treated with nicotine 2 mg/kg/d, 28 days	↓ Circulation of TNF-α and IFN-γ ↓ NF-κB transcription ↓ T-cell proliferation	Nizri et al. (2009)
In vitro LPS-induced inflammation in RAW264.7 macrophages	Incubation of GTS-21 1–10µM, 16 h	↓ Expression of TNF and HMGB1	Yang et al. (2019)
In vitro LPS-induced inflammation in isolated human peripheral monocytes and U937 monocytes	Incubation of nicotine 10µM, 1 h	↓ Expression of TNF-α, PGE2, and COX-2 ↓ IκBα phosphorylation ↓ NF-κB transcriptional activity	Yoshikawa et al. (2006)
In vivo encephalomyelitis induced in female C57Bl/6 mice	Treated with GAT-107 10 mg/kg/d, 9 days	↓ Circulation of IL-6, IL-17, and IFN-γ ↑ IL-10 ↓ Lymphocyte proliferation ↓ B-cells	Mizrachi et al. (2021)
In vivo TNBS-induced colitis in female CD1 Swiss mice	Treated with AR-17779 1.5 mg/kg	↓ Expression of IL-1β and IL-6 ↓ T-cells ↓ Macrophages	Grandi et al. (2017)
In vivo hydroxydopamine induced inflammation in male Wister rats	Treated with PNU-282987 3 mg/kg	↓ Expression of TNF-α and IL-1β ↑ α7nAChR expression	Jiang et al. (2020)

Abbreviations: α7nAChR, alpha 7 nicotinic acetylcholine receptor; ATP, adenosine triphosphate; HMGB1, high-mobility group box-1; IFN-γ, interferon gamma; IL, interleukin; LPS, lipopolysaccharide; mtDNA; mitochondrial DNA; NF-κB, nuclear factor kappa beta; PGE₂, prostaglandin E2; TNF-α, tumour necrosis factor alpha, ↑, increase; ↓ decrease.

3.1. Immune cells

Increased circulation and infiltration of immune cells (macrophages and lymphocytes) is a hallmark characteristic in the early phases of HFpEF (Bhagat et al., 2022; Strassheim et al., 2019). In brief, vascular endothelial and myocardial cell damage can favor the recruitment and infiltration of monocytes and macrophages into tissue, leading to the activation and amplification of local inflammatory mechanisms that can cause fibrotic remodeling and cellular death (Glezeva and Baugh, 2014; Hulsmans et al., 2018). Moreover, an influx of T-cells in damaged cardiac tissue has been implicated in chronic HFpEF development through the generation of autoimmune responses that facilitate vicious and unregulated cycles of inflammatory damage and fibrosis (Aghajanian et al., 2019; Blanton et al., 2019; Kalli et al., 2017).

It is well established that ɑ7nAChR is highly expressed on the surface of macrophages and T-cells, where it contributes to the regulation of inflammatory processes (Wang et al., 2003; Sato et al., 1999). Various publications have established that ACh, nicotine, and ɑ7nAChR agonists, such as GTS-21, inhibit the release of inflammatory cytokines (i.e., IL-1β, IL-6, IL-17, and TNF) from macrophages (Mizrachi et al., 2021; Abot et al., 2018; Garg and Loring, 2019). In the context of atherosclerosis, administration of GTS-21 was shown to reduced plaque size, which was associated with a decrease in circulating monocytes through reduced splenic extramedullary myelopoiesis and inflammation (Schloss et al., 2022; Al-Sharea et al., 2017). Moreover, it appears that activation of ɑ7nAChR in bone marrow stromal cells is required for normal hematopoiesis, and its deletion enhances myeloid cell production. Thus, activating the ɑ7nAChR produces effects that are therapeutically desirable for the treatment of HFpEF.

Indeed, the therapeutic potential of ɑ7nAChR restoring cardiac dysfunction has been shown through allosteric modulator PNU-282987, which protected mice from stroke-induced HF by modulating proliferation of macrophages away from an inflammatory phenotype and reducing subsequent cardiac expression of inflammatory mediators, including IL-1β, MCP-1, TNF, TLR4, and HMGB1 (Su et al., 2022). These effects were completely reversed by co-administration of receptor antagonist MLA (Su et al., 2022). T-cell accumulation within the heart is also a characteristic of both human and animal HFpEF, and is associated with the release of TNF and IFN-γ, which can upregulate signaling pathways to promote cardiac hypertrophy, fibrosis, and dysfunction (Huang et al., 2021; Kumar et al., 2022; Westermann et al., 2011). Inhibiting T-cell activation and infiltration has been suggested to be a viable therapy in the prevention of cardiomyocyte death in mice with HF (Kalli et al., 2017). The regulatory role of ɑ7nAChR in T-cell activation is supported by several studies demonstrating that receptor inhibition is associated with the activation and enhanced proliferation of pro-inflammatory T-cells (Nizri et al., 2006; Nizri et al., 2008; Zdanowski et al., 2015). Moreover, activation of ɑ7nAChR by GTS-21 has been shown to suppress isolated T-cell activation and reduces IFN-γ production (Wu et al., 2014), which may be therapeutically relevant in the mitigation cardiac fibrosis (Nevers et al., 2017). These studies demonstrate the immunosuppressive role of ɑ7nAChRs in modulating immune function through regulation of immune cells and cytokine production and may be relevant for targeting the hyper-inflammatory responses characterized by CVDs and HF.

3.2. Anti-inflammatory pathways

Nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) is a key transcription regulator that drives inflammatory, fibrotic, and apoptotic genes (Lee et al., 2003). Its activation can be triggered by RAAS, reactive oxygenated species, inflammatory cytokines, DAMPs, and TLR4 ligands (Liu T. et al., 2017; Chauhan et al., 2022; Cantero-Navarro et al., 2021). In CVD and diabetes-induced HFpEF models, cardiomyocyte NF-κB activation is linked to left ventricular remodeling and elevated expression of inflammatory cytokines and fibrotic factors (Hulsmans et al., 2018; Roche et al., 2015; Zuo et al., 2024). Consequently, NF-κB serves as a potential therapeutic target in HFpEF. ɑ7nAChR-mediated signaling has been shown to inhibit NF-κB activation, reducing the expression of IL-1β, IL-6, MCP-1, TNF-α, MCP-1, vascular adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule 1 (ICAM-1) (Zhang et al., 2013; Saeed et al., 2005). In hypertensive rats, the ɑ7nAChR agonist, PNU-282987, suppresses inflammation and protects against left ventricular damage and aortic thickening, partly through NF-κB inhibition (Li et al., 2011). These findings indicate the role of the ɑ7nAChR in regulating NF-κB as a mechanism for benefiting heart health.

Emerging evidence suggests that inflammasomes play a critical role in HFpEF (Li et al., 2022; Cheng et al., 2023). The Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a critical component of cardiac immune responses (Yao et al., 2018). In murine models of HFpEF, increased NLRP3 inflammasome activation is implicated in cardiomyocyte fibrosis, cardiac necrosis, left ventricular arrhythmia, and poor survival prognosis (Cheng et al., 2023; Yang HJ. et al., 2020). Given that inhibiting NLRP3 has been shown to improve left ventricular diastolic function and reduce cardiac inflammation and fibrosis in patients with HFpEF (Yang et al., 2024; Peh et al., 2023), it has emerged as a new target in HF management (Cheng et al., 2023). Although the role of ɑ7nAChR in cardiac NLRP3 regulation has yet to be investigated, neuroinflammatory and osteoarthritis models have demonstrated that receptor activation reduces NLRP3 activity to modulate pro-inflammatory responses. Furthermore, PNU-282987 has been reported to alleviate inflammation-induced aortic cell death dependent on NLRP3 inhibition (Fu et al., 2022), which may translate to cardiovascular protection against HFpEF.

HMGB1 acts as a DAMP to drive inflammation (Yang H. et al., 2020). In response to cellular stress, DAMPs are passively released from the nucleus of damaged cells to initiate an inflammatory response (Chen et al., 2022). Binding of HMBG1 to its receptors (e.g., TLR4 and RAGE) triggers inflammation and immune cell infiltration through NF-kB upregulation (Wahid et al., 2021; Oeckinghaus et al., 2011). Myocardial biopsies from HFpEF patients have shown significant upregulation of HMBG1 and TLR4 (Delalat et al., 2025). Mover, inhibiting HMGB1 expression in cardiac tissue of HFpEF mice reduces neutrophil infiltration and improves diastolic function (Zhang XL. et al., 2022). Consistent with a protective role of ɑ7nAChR through this pathway, agonism with GTS-21 has been demonstrated to attenuate hyperoxia-induced lung inflammation by reducing HMGB1 accumulation in serum, decreasing macrophage infiltration in lung tissue, and attenuating lung injury (Sitapara et al., 2020). Conversely, genetic deletion of ɑ7nAChR appeared to upregulate HMGB1 expression through an increase in NLRP3 activity (Lu et al., 2014). Interestingly, in a murine model of inflammation-induced chronic pain, central injection of ɑ7nAChR antagonist, α-BTX, exacerbated HMGB1 and NF-κB expression (Sun et al., 2022). Given these studies support the potential of ɑ7nAChR to regulate HMGB1 release, this pathway may provide another therapeutic anti-inflammatory strategy to combat HF.

4. α7nAChR and the RAAS

The RAAS is a major hormonal regulator of cardiovascular physiological and is instrumental in maintaining the homeostatic balance of blood pressure and systemic vascular resistance (Ruan et al., 2024). Overactivation of the RAAS is also a central component in the pathophysiology of HF, and drugs that target the RAAS have become important pillars of HF and CVD therapy (Ichikawa et al., 2025; Singhania et al., 2020). Angiotensin II (AngII) is the principal effector of the RAAS, and is synthesized by angiotensin-converting enzyme (ACE) within the classic axis of the RAAS, and exerts its tissue-dependent effects through the AngII type 1 receptor (AT₁R) to stimulate vasoconstriction, aldosterone release, and fluid retention in the kidneys (Ruan et al., 2024). Beyond its role in hemodynamic regulation, AngII/AT₁R signaling is well established in promoting cardiac inflammation through upregulation of NF-κB (Muller et al., 2000), NRLP3 (Espitia-Corredor et al., 2022), and HMGB1 (Zhang et al., 2021), resulting in fibrotic, apoptotic, and oxidative damage associated with HF (Beldhuis et al., 2017; Carter et al., 2024). Thus, it stands to reason that inhibition of this pro-inflammatory signaling pathway may be key to managing pathophysiological damage in HFpEF. Despite RAAS inhibitors (i.e., ACE inhibitors (ACEi) and AT₁R receptor blockers (ARBs) being commonly prescribed in patients with HF, the overall prognosis remains poor (Odajima et al., 2022; Kjeldsen et al., 2020).

Although the current understanding of ɑ7nAChR in RAS signaling remains limited, emerging evidence suggests that ɑ7nAChR may have a regulatory role in mitigating AngII/AT1R signaling. In neuronal cells, ɑ7nAChR plays a protective role in promoting cell survivability against AngII-induced stress (Shaw et al., 2003), while receptor against GTS-21 is shown to prevent AngII-mediated elevation of blood pressure, improve parasympathetic baroreflex control, and prevent pro-inflammatory NF-κB activation in response to AngII (Wu SJ. et al., 2021). Similarly, in a murine model of atherosclerosis, ɑ7nAChR agonist AR-R17779 reduces AT1R expression in vascular smooth muscle cells, suppressing AngII-mediated formation of atherosclerotic plaque (Hashimoto et al., 2014). This effect was also associated with a significant decrease in aortic tissue expression of IL-6, IL-1β, and pro-oxidative membrane complex NADPH oxidase (Hashimoto et al., 2014). The physiological importance of ɑ7nAChR in RAAS regulation is also observed in α7AChR^−/− mice, as deletion of this receptor exacerbates vascular injury in response to AngII infusion (Li et al., 2016). Importantly, this injury was alleviated in wild-type mice treated with PNU-282987, suggesting the important of ɑ7nAChR in regulation of AngII-mediated pathology (Li et al., 2016). Given that vascular injury is a major pathological phenotype of HFpEF, the ability of ɑ7nAChR to protect against AngII-induced vascular damage may be of crucial importance to its therapeutic value.

Angiotensin-converting enzyme-2 (ACE2) is a member of the counter-regulatory RAAS axis and is responsible for mitigating the deleterious actions of AngII/AT₁R and provides cardioprotective effects (Bhushan et al., 2023; Zisman, 2005). ACE2 degrades AngII into angiotensin 1–7 [Ang (Roth et al., 2020; Norhammar et al., 2023; Savarese et al., 2022; McDonagh et al., 2021; Dini et al., 2023; Thibodeau and Drazner, 2018; Naing et al., 2019)], which acts via the Mas1 oncogene receptor (MasR) to oppose the actions of AngII by promoting vasodilation through endothelial nitric oxide (NO) release (Fraga-Silva et al., 2013), reducing fibrosis, and mitigating pro-oxidative and pro-inflammatory signaling. Altered ACE2 expression/activity is directly linked to the progression of heart disease (Patel et al., 2016). Mice that lack ACE2 show elevated AngII and reduced Ang (Roth et al., 2020; Norhammar et al., 2023; Savarese et al., 2022; McDonagh et al., 2021; Dini et al., 2023; Thibodeau and Drazner, 2018; Naing et al., 2019) levels as well as an enhanced cardiac susceptibility to pathological ventricular remodeling, reactive oxygenated species accumulation, and an increase in pressure-overload-induced HF (Kassiri et al., 2009; Patel et al., 2014; Zhong et al., 2010). In contrast, overexpression of ACE2 in mice or treatment of rats with recombinant ACE2 protects the heart against myocardial injury and counteracts HFpEF, demonstrating the beneficial effects of enhancing ACE2 activity (Chamsi-Pasha et al., 2014; Zhao et al., 2010). In epithelial cells, cholinergic agonist, nicotine, is observed to upregulate ACE2 expression (Maggi et al., 2021), while silencing of the ɑ7nAChR gene attenuates this effect, suggesting a potential regulatory role of ɑ7nAChR signaling in promoting ACE2 expression (Cattaruzza et al., 2020). Furthermore, GTS-21 has been observed to significantly increase the ratio of ACE2 to ACE and shifts protein levels away from AngII/AT₁R towards Ang (Roth et al., 2020; Norhammar et al., 2023; Savarese et al., 2022; McDonagh et al., 2021; Dini et al., 2023; Thibodeau and Drazner, 2018; Naing et al., 2019)/MasR in murine models of chronic inflammation (Zhu et al., 2024). This effect has also been associated with inhibition of macrophage polarization, reduced NF-κB activation, and a decrease in IL-1β, Il-6, TNF-α, and HMGB-1 levels, suggesting a link between ɑ7nAChR and reduced pro-inflammatory signaling through enhanced RAAS regulation (Zhu et al., 2024). Collectively, these studies establish the potential regulatory role of ɑ7nAChR in RAAS signaling. Therapeutic strategies targeting ɑ7nAChR may therefore represent a promising approach to HFpEF by reducing cardiac inflammation, ventricular remodeling, and oxidative damage through coordinated suppression of ACE/AngII/AT1R and activation of ACE2/Ang (Roth et al., 2020; Norhammar et al., 2023; Savarese et al., 2022; McDonagh et al., 2021; Dini et al., 2023; Thibodeau and Drazner, 2018; Naing et al., 2019)/MasR pathway.

5. α7nAChR in hypertension and vascular regulation

Hypertension is the most prevalent comorbidity associated with HFpEF (Anker et al., 2021; Solomon et al., 2019). An increase in 1 mmHg systolic blood pressure >120 mmHg increases the risk of HFpEF by 3% in an acute HF setting (Styron et al., 2009). Hypertension causes a persistent pressure overload in the left ventricle, subsequently leading to left ventricular hypertrophy, fibrosis, stiffness, and eventual ventricular diastolic dysfunction (Guazzi et al., 2020; Mishra and Kass, 2021). Hypertension is also associated with sympathetic and RAAS overactivation, systemic inflammation, endothelial dysfunction, and immune cell recruitment into the myocardium, contributing to the progression of HFpEF (Levick et al., 2010). A comprehensive meta-analysis of 123 studies with over 600,000 participants has shown that a 10 mmHg reduction in blood pressure is enough to reduce the risk of HF by 28%; thus, controlling blood pressure is deemed critical to preventing the cardiovascular events of HF (Ettehad et al., 2016).

Baroreflexes are key regulators of autonomic cardiovascular stability and hemodynamic control (Clemmer et al., 2022). This system detects changes in blood pressure and relays this information to the CNS, which adjusts sympathetic autonomic outflow and RAAS activity to modulate peripheral resistance and cardiac output via changes in cardiac contractility, heart rate, and arterial vasoconstriction (Levick et al., 2010; Munoz-Durango et al., 2016). Baroreflex insensitivity stemming from autonomic dysfunction impairs blood pressure regulation and is a key feature in patients with resistant hypertension and HFpEF (Clemmer et al., 2022; Grassi et al., 2014). These patients exhibit a marked increase in sympathetic nerve activity, which is believed to contribute to the limited efficacy of ACEi or ARBs beyond blood pressure reduction (Georgakopoulos et al., 2011; Yaxley and Thambar, 2015). Clinical studies have shown that promoting a shift from sympathetic innervation at the baroreceptor level is favorable to improving cardiac efficiency and reducing adverse remodeling to combat HFpEF (Mazidi et al., 2017; Seravalle et al., 2019). Hypertensive models have shown that baroreflex dysfunction is closely linked with decreased tissue expression of ɑ7nAChR and elevated circulation of inflammatory mediators (Guo et al., 2017; Chen et al., 2012). Moreover, ɑ7nAChR deficiency is observed to exacerbate baroreflex dysfunction (Liu et al., 2012). Pharmacological activation of ɑ7nAChR has been demonstrated to mitigate baroreflex dysfunction and alleviate hypertension-induced end-organ damage (Li et al., 2011; Guo et al., 2017). Most importantly, vagal nerve stimulation has been shown to effectively attenuate blood pressure elevation in hypertensive rats to the same degree as the clinically prescribed ARB, Olmesartan. This effect was dependent on ɑ7nAChR, as demonstrated by its attenuation with receptor antagonist MLA (Elkholey et al., 2022).

In addition to central regulation of cardiovascular hemodynamics, the ɑ7nAChR has also been implicated in local cardiac cholinergic signaling. Positive CHRNA7 protein and ɑ7nAChR expression has been detected in cardiac tissue, localized to cardiac fibroblasts, neurons, and cardiomyocytes (Li et al., 2019; Dvorakova et al., 2005). Here, functional studies have indicated that the receptor may participate in local cholinergic regulation of the heart under specific stress conditions. In Langendorff preparations of the isolated rat heart, nicotine-induced bradycardia was blocked by the ɑ7nAChR antagonist, ɑ-BTX (Ji et al., 2002). Other studies have demonstrated that receptor antagonist, MLA, attenuates cardiac sympathetic pressor responses with no effect on bradycardia responses (Li et al., 2009). These results are consistent with α7AChR knockout models, showing that receptor deletion has no effect on baroreflex (Franceschini et al., 2000) and vagal simulation-induced bradycardia (Deck et al., 2005). A slight reduction in heart rate has been observed in mice lacking α7AChR, only following cardiac exposure to high ACh concentrations (Targosova et al., 2024), suggesting that cardiac α7AChR plays a direct role in local cholinergic overstimulation. This is supported by studies in Schwann cells (key component of neuromuscular junction), which show that α7AChR reduces ACh release following inhibition of cholinesterases (Petrov et al., 2014). Furthermore, in rats with myocardial infarction-induced chronic HF, AChE inhibitor, donepezil, significantly enhanced vagal tone, improved heart rate and cardiac function, as well as reducing cardiac remodeling, fibrosis, and inflammation The role of ɑ7nAChR in cholinergic regulation of the heart and anti-inflammatory signaling has also been linked to cholinesterases, such as AChE and BChE. While AChE is classically associated with synaptic ACh hydrolysis, BChE is abundant in non-neuronal tissue and contributes substantially to ACh degeneration in the heart (Dingova et al., 2025). Reduced ACh availability has been associated with early onset CVDs, contributing to increased cardiac mortality and impaired myocardial regeneration (Liu et al., 2024). These alterations are linked to autonomic cardiovascular dysregulation, enhanced AngII/AT₁R signaling (Xu et al., 2018; Liu et al., 2011), and myocardial oxidative and inflammatory damage. AChE and BChE are both expressed in the atrial and ventricles (Dingova et al., 2025; Kilianova et al., 2020), and elevated circulation of these enzymes has been reported in major HF risk factors, including obesity and type II diabetes (Villeda-Gonzalez et al., 2024). AChE and BChE activity are key determinants of local Ach bioavailability, with BChE contributing significantly to ACh hydrolysis in the cardiac tissue. Thus, these enzymes are suggested to play a fundamental role in ɑ7nAChR signaling (Dingova et al., 2025). At the cellular level, suppression of AChR and BChR mRNA increases ɑ7nAChR expression, leading to an enhanced anti-inflammatory response (Nadorp and Soreq, 2015). Furthermore, ɑ7nAChR activation triggers intracellular calcium ion influx which inhibits AChE expression in macrophages, suggesting the presence of a feedback mechanism regulating local cholinergic tone (Liu et al., 2020). This potential feedback mechanism is also supported by investigations at the neuromuscular junction where ɑ7nAChR activation inhibits further release of ACh (Petrov et al., 2025).

Capillary rarefaction refers to a reduction in capillary density and shows a close association with the functional decline of the left ventricle in HFpEF patients (Mohammed et al., 2015). Multiple studies in hypertensive modes show diminished left ventricle capillary density, and is strongly associated with inflammation and RAAS overactivation (Gonzalez et al., 2015; Ihori et al., 2016; Yazawa et al., 2011). An increase in systemic circulation of pro-inflammatory cytokines and AngII can lead to heart capillary rarefaction through endothelial dysfunction and a subsequent reduction in NO and cyclic guanosine monophosphate bioavailability, which inhibits vasodilation and favors oxidative and fibrotic cardiac damage (Franssen et al., 2016; Tam et al., 2017). ɑ7nAChR expression on vascular cells has been established (Wada et al., 2007; Conti-Fine et al., 2000; Heeschen et al., 2002)regulate cellular proliferation, inflammation, oxidative stress, and increase cell survival (Vieira-Alves et al., 2020; Liu L. et al., 2017). In cultured endothelial cells, ɑ7nAChR agonist, PNU-282987, has been observed to increase endothelial NO synthase expression/activity, resulting in the subsequent production of NO (Wu et al., 2023). This was prevented by the antagonist, MLA. Neuronal cells have also demonstrated ɑ7nAChR-dependent coupling of NO synthase to promote NO production (Haberberger et al., 2003). This increase in NO bioavailability may be associated with enhanced Sirtuin-1 production. Sirtuin-1 is a protein deacetylase known to have a beneficial role in cardiovascular health through increased vascular eNOS expression and increased cardiac capillary density (Askin et al., 2020; Xia et al., 2013), for which PNU-282987 has been shown to promote in isolated mouse vascular cells, leading to the prevention of oxidative stress and proliferative arrest (Li et al., 2016). Moreover, nicotine is observed to enhance capillary density in the ischemic heart of myocardial infarction-induced rats, which was inhibited by both MLA and α-BTX (Li and Wang, 2006). Since endothelial dysfunction and impaired NO signaling are pathological phenotypes of HFpEF patients, these studies suggest that ɑ7nAChR may participate in vasoprotective effects that improve vascular tone and capillary formation, underscoring it as a promising therapeutic target to restore cardiovascular regulation in HFpEF.

6. α7nAChR in metabolic regulation

Metabolic dysfunction is a major contributor to HFpEF. Unlike HFrEF, HFpEF is strongly associated with metabolic disorders such as obesity and Type II diabetes (Jackson et al., 2022; Pandey et al., 2017; Prausmuller et al., 2023). These comorbidities can contribute to the overlap between chronic inflammation, sympathetic nervous system and RAAS activation, endothelial dysfunction and hypertension, leading to pathogenic myocardial remodeling and stiffness (Borlaug et al., 2023; van Dalen et al., 2025). While traditional HF therapies, including RAAS inhibitors and mineralocorticoid antagonists, show limited benefit in metabolic comorbidities linked to HFpEF (Borlaug et al., 2023), recent clinical investigations targeting these pathways, such as SGLT2 inhibitors (Solomon et al., 2021; Anker et al., 2021), statins (Alehagen et al., 2015; Schiattarella et al., 2021), and weight loss (Savji et al., 2018; Kitzman et al., 2016) are linked with a significant reduction in HF hospitalization and mortality, underscoring the importance of metabolic regulation in HFpEF management.

Recent studies highlight a protective role of ɑ7nAChR in metabolic disorders. In high-fat-fed obese mice and obese patients, ɑ7nAChR mRNA and protein levels are markedly reduced compared with normal-weight controls (Cancello et al., 2012; Li et al., 2018). Receptor deficiency in high-fat animals is also associated with severe chronic low-grade inflammation (Souza et al., 2019), whereas activation downregulates inflammatory gene expression and limits adipose macrophage infiltration (Chang et al., 2019; Pavlov and Tracey, 2012). A decrease in adipose tissue inflammation is strongly associated with improvements in hypertension and vascular dysfunction (Chait and den Hartigh, 2020; Jin et al., 2023). In AngII-accelerated atherosclerotic mice on a high-fat diet, the ɑ7nAChR agonist, AR-R17779, lowered blood pressure, reduced circulating lipids, IL-6, and TNF, and improved survival (Hashimoto et al., 2014). Additionally, ɑ7nAChR activation by GTS-21 has been shown to enhance glucagon-like peptide-1 (GLP-1) activity, a hormone involved in glucose regulation, appetite suppression, and cardiovascular inflammation (Xie et al., 2020). Providing some insight into a mechanistic link and outcomes, early clinical and experimental data suggest GLP-1 activation provides protective cardiovascular effects against HFpEF (Cimino et al., 2024; Butler et al., 2023). Collectively, these studies suggest that ɑ7nAChR activation could provide beneficial effects in HFpEF by improving metabolic regulation and attenuating associated inflammation.

7. Perspectives and conclusion

Over time, evidence has mounted to build a compelling case that HFpEF is a multifactorial disorder hallmarked by several mechanisms, including inflammation, endothelial dysfunction, potentiated by hypertension and metabolic disorders. As such, new therapies that are effective across this broad spectrum of pathologies are required. This review highlights substantial evidence supporting the physiological importance and therapeutic potential of α7nAChR in HF and HFpEF management. In cases where, ACEi, ARBs, or other antihypertensive agents only partially benefit, ɑ7nAChR activation may offer complementary cardioprotective effects against HFpEF through its direct or indirect regulation of systemic and local cardiovascular inflammation through NF-κB/NLRP3/HMGB1 suppression, changes in RAAS classical and alternative axis components, improved baroreflex and vascular signaling, and modulation to metabolic and neural pathways to mitigate cardiac damage and alleviate comorbidities associated with HF, such as obesity, dyslipidemia, and hypertension. Future studies are needed to identify the most effective and well-tolerated α7nAChR agonist and to determine the clinical significance of targeting this receptor in patients. Additionally, studies should seek to further characterize the physiological importance of central and peripheral α7nAChR in cardiovascular regulation, as well as the therapeutic efficacy between orthostatic and PAM receptor agonism, given their differences in receptor desensitization, tissue specificity, and reliance of endogenous ACh cholinergic signaling.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. JS and LG would like to acknowledge the Institute of Health and Sport, Victoria University, for their support as JS and LG are recipients of Victoria University postgraduate scholarship (DOI: https://doi.org/10.82133/C42F-K220).

Author contributions

JS: Writing – original draft, Writing – review and editing. LG: Writing – original draft, Writing – review and editing. SH: Writing – review and editing. BR: Writing – review and editing. AM: Writing – review and editing. VA: Writing – review and editing. AZ: Writing – original draft, Writing – review and editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors XY, ZZ declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision.

Correction note

A correction has been made to this article. Details can be found at: 10.3389/fphar.2026.1841172.

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