Transient receptor potential vanilloid type 1: cardioprotective effects in diabetic models

ABSTRACT

Cardiovascular disease, especially heart failure (HF) is the leading cause of death in patients with diabetes. Individuals with diabetes are prone to a special type of cardiomyopathy called diabetic cardiomyopathy (DCM), which cannot be explained by heart diseases such as hypertension or coronary artery disease, and can contribute to HF. Unfortunately, the current treatment strategy for diabetes-related cardiovascular complications is mainly to control blood glucose levels; nonetheless, the improvement of cardiac structure and function is not ideal. The transient receptor potential cation channel subfamily V member 1 (TRPV1), a nonselective cation channel, has been shown to be universally expressed in the cardiovascular system. Increasing evidence has shown that the activation of TRPV1 channel has a potential protective influence on the cardiovascular system. Numerous studies show that activating TRPV1 channels can improve the occurrence and progression of diabetes-related complications, including cardiomyopathy; however, the specific mechanisms and effects are unclear. In this review, we summarize that TRPV1 channel activation plays a protective role in the heart of diabetic models from oxidation/nitrification stress, mitochondrial function, endothelial function, inflammation, and cardiac energy metabolism to inhibit the occurrence and progression of DCM. Therefore, TRPV1 may become a latent target for the prevention and treatment of diabetes-induced cardiovascular complications.

KEYWORDS:

• Transient receptor potential vanilloid type 1
• diabetes
• cardiovascular complication
• oxidative stress
• inflammation
• endothelial function

Introduction

Diabetes is a systemic metabolic disease usually associated with hypertension, hyperlipidemia, hyperuricemia, obesity, and heart failure (HF) [1]. Diabetes is considered a risk factor for cardiovascular disease, a major cause of increased mortality among patients with diabetes [2]. Data from China demonstrate that 30% of patients with diabetes experience adverse cardiovascular events, accounting for 20% of all mortalities among this population [3]. Diabetes and HF often coexist and are closely related; diabetes increases the risk of HF, and the evaluation, treatment, and prognosis of patients with HF are worse in the context of diabetes [4]. The epidemiological link between diabetes and HF was confirmed in the 1974 Framingham study. After adjusting for relevant risk factors (such as age and concomitant complications), diabetes increased the incidence of HF by 2.5-fold in men and by 5-fold in women [5]. Diabetes accounts for 1/3 of the total number of patients in clinical studies related to HF and is an independent risk factor for poor prognosis [6–8]. Due to the accelerated aging of the population, diabetes-related HF has become prevalent worldwide [9] and threatens the lives and health of people with diabetes.

Characteristics of a diabetic heart

As early as 1972, the autopsy pathology of four patients found that [10] they showed symptoms of HF, with no evidence to support coronary or valvular disease. This is defined as myocardial structural changes and ventricular dysfunction unrelated to other cardiac risk factors, namely diabetic cardiomyopathy (DCM) [11,12]. Generally, this is a kind of myocardial disease that occurs in patients with diabetes and cannot be attributed to conditions like hypertension, coronary atherosclerotic heart disease and other heart diseases. Patients often have clinical manifestations such as angina, arrhythmia and even HF. In an experimental animal model of diabetes, it was also found that diastolic and systolic functions of the heart decreased, accompanied by a decrease in the contraction of cardiomyocytes and variations in the level of specific cardiomyocyte proteins [13,14]. Later studies further found that DCM is characterized by 1) increased myocardial fibrosis and hardness and 2) increased atrial enlargement and left ventricular end-diastolic pressure [15]. The exact cause of diabetes-related cardiac dysfunction is unclear. Still, many basic contributing factors have been reported, including cardiac fibrosis, cardiac hypertrophy, endothelial dysfunction, oxidative stress, inflammation, and mitochondrial dysfunction [16] (Figure 1). The increased apoptosis and autophagy damage caused by these disorders are also related to cardiac remodeling in DCM [17].

Figure 1. Basic mechanism of diabetes cardiomyopathy. Systemic hyperglycemia, insulin resistance, and deposition of advanced glycation end products (AGEs) caused by diabetes can induce cardiac metabolic changes, promote myocyte inflammation, endothelial cell damage, and mitochondrial dysfunction. These pathways interact with each other, directly or indirectly leading to cardiac hypertrophy, fibrosis, and ischemia, ultimately leading to dysfunction of cardiac relaxation and contraction.

Cardiac insufficiency in patients with diabetes is usually asymptomatic and subclinical in the early stages and is not detected until the terminal stage [18]. It then develops into severe diastolic dysfunction with a normal ejection fraction and eventually into systolic dysfunction in clinical HF with a decreased ejection fraction [11]. Even in asymptomatic patients with good blood glucose control, about 50% showed some degree of cardiac insufficiency [19,20]. Therefore, early diagnosis and treatment of diabetic cardiac complications are required. The current treatment strategy focuses on blood sugar regulation. At the same time, there is a lack of specific treatment and effective clinical management for the diabetic heart, although the sodium-glucose cotransporter-2 inhibition [SGLT2i] offers some hope in this regard [21,22]. Therefore, the need for effective prevention and treatment of cardiovascular complications related to diabetes is important.

Transient receptor potential vanilloid type 1

The transient receptor potential cation channel, subfamily V member 1 (TRPV1), is a nonselective cation channel with obvious permeability to ions, such as H+, Na+, Ca2+, and Mg2+ [23]. The TRPV1 channel comprises four subunits, each containing six transmembrane helices [24]. TRPV1 channels exist as tetramers with C and N terminals facing the cytoplasmic surface [25]. The channel can be activated by a variety of physical or chemical substances, such as temperatures (>42°C), low pH, capsaicin, arachidonic acid, bradykinin, cannabinoids, and free radical metabolites [26,27].

TRPV1 channels are widely distributed in various organs, such as the lung, liver, kidney, intestine, and brain [28], as well as in the cardiovascular system, such as cardiomyocytes [29], epicardium [30], sensory nerve fibers innervating the myocardium [31], vascular endothelial cells, and smooth muscle cells (Table 1) [28]. However, some studies have demonstrated no expression of TRPV1 in cardiomyocytes [32,33]. Such differences may be owing to different sensitivities of antibodies used in immunocytochemical approaches or inappropriate signal to noise ratio. Additionally, recent data show that the sensitivity of TRPV1 channels to agonist activation can be regulated by TRPA1 channel agonists [34]. When two receptors are co-expressed in the same cell, there is a crosstalk between them. The primary finding of the study is the absence of functional TRPA1 and TRPV1 in murine cardiomyocytes [32]. Further research is required to determine the expression and degree of TRPV1 in cardiomyocytes, as well as whether it experiences interference from other receptor channels.

Table 1. Expression of TRPV1 in Cardiovascular system and its effect on cardiovascular system after activation.

Cellular Localization	Experimental model	Mechanism	role/effects on activation in Cardiovascular System	References
Endothelial cells
Aorta endothelial cells	WT and TRPV1^−/− mice	Increased eNOS phosphorylation and NO production, vasorelaxation	Vasorelaxation, lower blood pressure, Beneficial	Yang et al [35].
Aorta endothelial cells	WT and TRPV1^−/− mice	Trigger AMPK-dependent signaling, increased eNOS phosphorylation and NO bioavailability	Promote angiogenesis and improve endothelial function, retard atherogenesis, Beneficial	Qing et al [36].
Vascular endothelial cells	Deoxycorticosterone-salt hypertensive mice	Attenuate cytokine and chemokine production, adhesion molecule expression, activation of NF-κB, and monocyte adhesion	Inhibition of endothelial cell inflammation, Beneficial	Wang et al [37].
Smooth muscle cells
Aorta vascular smooth muscle cells	Male ApoE^−/− and ApoE^−/− TRPV1^−/− mice	Reduce LRP1 expression in vascular smooth muscle cell by calcium-dependent and calcineurin- and protein kinase A-dependent mechanisms	Increase cellular cholesterol efflux and reduce cholesterol uptake, attenuate atherosclerosis, Beneficial	Ma et al [38].
Coronary artery vascular smooth muscle cells	Chronic kidney disease mice and high phosphate-induced vascular smooth muscle cells calcification models	Deacetylation and degradation of Hif1α by upregulating SIRT6, inhibits osteogenic transdifferentiation	Protect against arterial calcification, Beneficial	Luo et al [39].
Pulmonary artery smooth muscle cells	Normoxic rat, cultured these cells under in vitro hypoxia	Activate the myosin ATPase in a Ca^2+ -calmodulin -myosin light chain kinase -myosin regulatory light chain pathway, stimulate transcription factors	Vascular contraction, proliferation and migration, pulmonary hypertension, Detrimental	Thibaud et al [40].
Cardiomyocytes
Cardiomyocytes	TRPV1^−/− and WT mouse, hypoxia/reoxygenation induced apoptosis of H9C2 cardiomyocytes	Increase in intracellular calcium levels leading to increased mitochondrial superoxide production and depolarization of the mitochondrial membrane potential	Mitochondrial dysfunction, exacerbate cardiomyocytes apoptosis, Detrimental	Sun et al [41].
Cardiomyocytes	WT or TRPV1-/- mice on high-salt diet	Upregulate PPAR-δ and UCP2 protein expression and decreased iNOS production; relieved oxidative/nitrotyrosine stress	Attenuate myocardial hypertrophy and fibrosis, Beneficial	Gao et al [42].
In both the mitochondria and cytoplasm of cardiomyoblasts	WT or TRPV1-/- mice on high-salt diet	Protect mitochondria from dysfunction by increasing cardiac mitochondrial SIRT3 expression, ATP production and Complex I enzyme activity	Attenuate myocardial hypertrophy and fibrosis, improve cardiac dysfunction, Beneficial	Lang et al [43].
Primary cardiomyocytes	WT or TRPV1-/- mice, an in vivo rat myocardial infarction model	Regulate mitochondrial membrane potential, maintain mitochondrial integrity during states of cellular stress	Reduce myocardial reperfusion injury, Beneficial	Carl et al [29].
Cardiomyocytes	C57 mice with TAC	TRPV1 is a physical component of the natriuretic peptide A, cGMP, and PKG signalling complex	Myocardial hypertrophy, Detrimental	Jaime et al [44].
Cardiomyocytes	Cardiomyocytes isolated from C57 mice were subjected to hypoxic stress	AMPK signaling is activated, improve autophagy flux	Mitigate hypoxic injury in cardiomyocytes, Beneficial	Wei et al [45].
Sensory nerve fibers
Sensory nerve fibers innervating the myocardium	WT or TRPV1-/-mice with TAC	Increase the release of CGRP, thereby reducing the secretion of inflammatory mediators, including TNFα and IL-6	Attenuate cardiac inflammation and myocardial hypertrophy, improve cardiac function, Beneficial	Zhong et al [46].
Sensory nerve fibers innervating mesenteric resistance arteries	WT or TRPV1-/-mice	Depolarization of nerve fibers, SP is released from these neurones and bind to tachykinin NK1 receptors	Constriction of vascular smooth muscle, Beneficial	Ramona et al [47].
Cardiac afferent neurons	Male spontaneous hypertensive rats	Chronically drive sympathoexcitation, adverse myocardial remodeling	Electrical heterogeneity, increase Ventricular tachycardia/fibrillation risk, Detrimental	Koji et al [30].

WT: wild-type; TRPV1^−/−: TRPV1 knockout; eNOS: endothelial Nitric Oxide Synthases; NO: Nitric Oxide; AMPK: AMP-activated protein kinase; NF-κB: nuclear transcription factor-κB; Hif1α: Hypoxic-Inducible Factor-1 Alpha; SIRT3: Sirtuin 3; SIRT6: Sirtuin 6; LRP1: low-density lipoprotein-related protein 1; PPAR-δ: peroxisome proliferator-activated receptor δ; UCP2: Uncoupling protein 2; PASMC: pulmonary artery smooth muscle cells; TAC: transverse aortic constriction; cGMP: cyclic adenosine monophosphate; CGRP: calcitonin gene-related peptide; SP: substance P; TNFα: tumor necrosis factor α; IL-6: Interleukin-6; NK1: Neurokinin-1.

Activation of this channel can lead to the release of neurotransmitters from peripheral nerve endings, including substance P (SP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase‐activating polypeptide (PACAP), somatostatin (SST) and other neuropeptides resulting in cardiovascular response [48,49] (Figure 2). These neuropeptides play crucial roles in the heart both locally (local efferent function) and via the bloodstream (systemic efferent function) [50]. Moreover, CGRP can dilate blood vessels and reduce blood pressure by increasing intracellular NO and K concentrations through endothelial and non-endothelial dependent mechanisms. CGRP can also lower blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system [51].

Figure 2. Schematic diagram of CGRP and SP release caused by TRPV1 activation. Substance P and CGRP-positive dorsal root ganglia (DRG) neurons often co-express transient receptor potential vanilloid (TRPV1) channel. When TRPV1 is activated, the conformation of TRPV1 changes, the channel opens, the permeability to cations (mainly Ca2+) increases, 1) the influx of cations such as Ca2+ produces depolarizing action potential;2) CGRP is packaged and co-released with substance P in a calcium dependent manner due to depolarization or increased intracellular calcium.

The potential protective functions of TRPV1 on the cardiovascular system are being increasingly recognized. Earlier studies have found that a variety of neurotransmitters released by TRPV1 can directly protect the heart against damage [52], protect the heart from the adverse effects of ischemic stress [52], improve coronary artery dysfunction, prolong the lifespan of atherosclerotic mice [53], and inhibit oxidative stress caused by high salt-induced hypertension [54].

Our review sums up the cardiovascular effects of TRPV1 in diabetic models, which are believed to be related to the occurrence and development of DCM. Hopefully, this information will help evaluate the cardioprotective effect of TRPV1 in diabetic models.

TRPV1-mediated cardioprotective mechanism in diabetic models

Inhibition of oxidative stress

Oxidative stress is an imbalance between excessive reactive oxygen species (ROS) production and degradation capacity, which tends to be in an oxidative state, leading to inflammatory infiltration in the body and an important factor in cell aging and disease. As the antioxidant content of the normal heart is lower than that of other organs, the heart is extremely vulnerable to oxidative stress and injury [55,56]. Cardiac ROS are mainly derived from uncoupled nitric oxide (NO) synthase, mitochondrial respiratory chain, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which can be triggered by diversified stimuli, such as tumor necrosis factor-α (TNF-α), angiotensin II (Ang-II) and endothelin-1 (ET-1) [57,58]. In the initial phase of diabetes, multiple antioxidants in the heart are likely to be upregulated to compensate; however, in the late period, diabetes not only produces additional ROS and/or reactive nitrogen species (RNS), but also, more importantly, compromises the antioxidant capacity of the heart [59,60]. Overall, unbridled plasma glucose levels and low-grade systemic inflammation trigger excessive oxidative stress in the cardiovascular system [61]. Increased ROS levels increase the possibility of arrhythmias [62], especially in structurally impaired left ventricular hypertrophic heart disease like DCM [63].

Uncoupling protein 2 (UCP2), a member of the mitochondrial anion carrier family, is a physiological regulator of mitochondrial ROS production and may help prevent diabetes [64,65]. One study demonstrated that oxidative stress induces the expression of UCP2, which prevents the production of ROS. ROS modulates diverse signal trans duction pathways, leading to increased expression of cell adhesion molecules, initiation of pro-inflammatory pathways, activation of matrix metalloproteinase, vascular smooth muscle cell proliferation and death, and endothelial dysfunction and lipid peroxidation – factors implicated in atherogenesis. Therefore, augmented UCP2 activity might restrict ROS production, thereby reducing the hazard of atherosclerosis in patients with diabetes [66]. Studies have indicated that the administration of capsaicin or its analogues can increase the expression of UCP2 in fatty and liver tissues [67,68]. In addition, Sun et al. [69] found that capsaicin could reverse the decrease in TRPV1 expression and protein kinase A (PKA) phosphorylation in endothelial cells induced by high blood sugar and reduce the level of ROS through the PKA/UCP2 pathway. This study further found that compared with normal glucose exposure, high glucose culture impaired endothelium-dependent relaxation of aortic rings in Wild Type (WT) and TRPV1 knockout (TRPV1-) mice. Capsaicin improved endothelium-dependent relaxation of the aortic rings in WT mice but has no effect on TRPV1- mice. We conclude that dietary capsaicin-activated TRPV1 stimulates endothelial PKA phosphorylation, motivates UCP2 expression, inhibits oxidative stress, and promotes endothelial-dependent relaxation in diabetic mice.

Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant genes [70]. In previous studies, Nrf2 not only regulates ROS levels in normal hearts but also plays a part in diabetic hearts [71]. It was further reported that the Nrf2 expression was precipitously downregulated in the hearts of diabetic animals and patients [72]. The downregulation of Nrf2 is an important cause of various diabetic complications [73–75], which may partly explain the occurrence and progression of DCM. It has been found that the influx of Ca2+ produced by TRPV1 activation enhances the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), which then further upregulates Nrf2 [76]. Therefore, we speculated that TRPV1 may improve oxidative stress in diabetic hearts by upregulating Nrf2 expression.

Alleviating endothelial dysfunction and microvascular injury

Chronic and recurrent hyperglycemia can increase endothelial oxidative metabolism and reduce the bioavailability of NO, an endothelium-derived vasodilator [77]. The endothelium of the arterioles maintains the contractile and diastolic function of the blood vessels through “real-time monitoring” of the blood flow, and further regulates the blood pressure of the body and the pumping blood of the heart. Additionally, endothelium protects body tissues from toxic substances and plays a pivotal role in regulating blood coagulation, maintaining electrolyte balance and facilitating substance transport between tissues and organs. Impairment of these endothelial functions, often leads to vascular dysfunction, which is associated with heart disease. Endothelial dysfunction is inextricably linked to the evolution and degree stratification of cardiovascular diseases in patients with diabetes [78]. In the pathogenesis of decreased NO bioavailability and endothelial dysfunction caused by diabetes and obesity, disturbances in calcium handling in endothelial cells make a critical difference in disturbing the dynamic balance of endothelial cells. Substantial evidence suggests that Transient receptor potential (Trp) channels are involved in calcium regulation in endothelial cells and to be pivotal in vascular dysfunction caused by obesity and diabetes [79].

Li [80] pointed out in a study that model mice with Type 2 Diabetes Mellitus (T2DM) showed 1) decreased expression of TRPV1 in cardiac microvascular endothelial cells (CMECs); 2) inhibition of mitochondrial function, such as the production of ATP and decrease in mitochondrial membrane potential; 3) decreased production of endothelial NO and increased apoptosis of endothelial cells; and 4) destruction of cardiac microvascular integrity, such as irregular valgus and invagination. Impaired diastolic function, such as a decrease in the ratio of the early mitral diastolic wave to the late mitral diastolic wave, showed more severe microvascular damage and diastolic dysfunction in TRPV1- diabetic mice. After supplementation with the OPA1 gene in vitro, the damage of TRPV1- to vascular endothelial cells in diabetes partially improved. Capsaicin noticeably added the mRNA expression of TRPV1, PGC-1a, and OPA1 in the CMEC of WT mice but this phenomenon was not seen in TRPV1- mice. It can be seen that capsaicin activates TRPV1 to reduce the microvascular injury of the diabetic heart through the PGC-1/OPA1 signal.

Additionally, capsaicin-activated TRPV1 can improve the proliferation, migration, and oxidative stress of vascular smooth muscle cells lured by oxidized LDL by upregulating the expression of peroxisome proliferator-activated receptor (PPAR) α and retarding vascular remodeling [81]. Zhu et al. pointed out [82] that the aging of blood vessels is accelerated in patients with diabetes compared to healthy individuals. Capsaicin increases Silent mating type information regulation 2 homolog-1 (SIRT1) levels through the TRPV1/[Ca 2 +] i/CaMKII/AMPK channel. It downregulates the aging marker p21, thus insulating endothelial cells from senescence caused by intermittent hyperglycemia, such as alleviating G0/G1 stagnation, increasing cell viability, and reducing senescent cell counts and ROS production.

Inhibition of inflammation

Inflammation is a self-defense response that occurs when the body is exposed to various damaging factors. Chronic low-grade inflammation is the “common soil” of diabetes and cardiovascular disease. Diabetes is a systemic low-grade inflammatory disease. Hyperglycemia directly induces the secretion and upregulation of cytokines, chemokines, and adhesion molecules in cardiomyocytes by regulating diversified signal pathways, which are based on the nuclear factor kappa-B (NF- κ B) [83–85]. NF-κ B is one of the critical transcription factors regulating pro-inflammatory cytokines, pro-fibrosis genes, and cell survival expression [86]. After these basic molecular events, leukocytes infiltrate the myocardium and increase ROS production by secreting cytokines and fibrogenic factors, thus perpetuating the inflammatory process [83–85]. Additionally, activation of the renin-angiotensin-aldosterone system and advanced glycation end products mediates the aseptic inflammation of cardiomyocytes of patients with diabetes, mainly by acting on Toll-like receptors (TLR) [87–89].

It has been reported that the inhibition of inflammation can improve cardiac insufficiency in diabetic hearts [90]. Still, the absence of TRPV1 can enhance local inflammation and accelerate the attack of systemic inflammatory response syndrome [91]. A study [37] suggested that TRPV1 inhibits the endothelial cells inflammation by activating eNOS, which is characterized by the production of proinflammatory cytokines/chemokines and decreased expression of adhesion molecules. The findings as well showed that TRPV1 induces these effects through activating the Ca2±dependent PI3K/Akt/eNOS/NO signaling pathway and inhibiting NF-κB, which is in accordance with the report of Ching [92]. Furthermore, endovanilloids, a TRPV1 activator, can curb the activation of NF-κB and nuclear factor of activated T cells (NFAT) [93,94]. Huang et al. also pointed out that the deletion of TRPV1 can increase inflammation after myocardial infarction [95].

What’s more, diabetes can promote the tissue infiltration of macrophages and polarize them to M1-like “pro-inflammatory” phenotypes [96,97]. Lv et al. uncovered that TRPV1 inhibits the polarization of M1 macrophages during the progression of osteoarthritis [98]. Zhao et al. certified that the activation of TRPV1 is able to prevent lipid accumulation induced by oxidized LDL and macrophage inflammation induced by TNF-α [99]. Therefore, TRPV1 may alleviate inflammation in the diabetic heart by suppressing the polarization of M1 macrophages.

Improving the function of mitochondria

Of the intracellular ATP in cardiomyocytes, 90% are produced by mitochondrial oxidative phosphorylation; however, in T2DM, mitochondria convert from glucose oxidation to Free Fatty Acids oxidation to produce ATP [18], accompanied by boosted mitochondrial ROS production, damaged oxidative phosphorylation, and calcium overload, resulting in mitochondrial respiratory dysfunction and further autophagy and necrosis of cardiomyocytes [100,101]. Mitochondrial dysfunction is of great importance in the development of DCM and related HF [102].

Luo et al. pointed out [103] that dietary capsaicin upregulates the expression of PGC-1α by activating TRPV1, which increases the quality of mitochondria, improves the respiratory function of mitochondria, and promotes the transformation of glycolysis type II fibers to more oxidizing type I fibers. Previous studies have shown that because type I fibers have more mitochondria, they produce more ATP from lipid oxidation but less ATP from glycolysis than type II fibers, thus offering stabilized energy over a lasting period and reducing lactic acid stockpile [104,105].

In addition, research by Wu et al. found that [106,107] hyperglycemia decreased the activity of AMP-activated protein kinase (AMPK) and triggered the formation of abnormal MAM mitochondrial-associated endoplasmic reticulum (MAM) mediated by Fundc1, leading to mitochondrial dysfunction and cardiomyopathy. Previous studies have shown that Fundc1, a mitochondrial extracellular protein, is of great significance for mitochondrial autophagy and MAMs [107]. Recently, Xiao et al. [108] reported that TRPV1 activation antagonized diabetic nephropathy by reducing Fundc1 transcription and improving mitochondrial function. Therefore, it can be speculated that the activation of TRPV1 can also antagonize DCM by improving Fundc1-related mitochondrial function.

Reduced myocardial fibrosis and cardiac hypertrophy

The earliest autopsy and biopsy evidence showed that an arresting increase in type I and III interstitial collagen deposition in patients with diabetes match non-diabetic myocardial biopsies [109]. Increased expression of TGF-β was reported in diabetic animal models, and this phenomenon was associated with cardiac fibrosis [110–112]. Related studies have found that the TGF-β signal transduction pathway leads to diabetic cardiac fibrosis by inducing cardiomyocyte apoptosis [113], stimulating excessive production of fibroblasts [114], and increasing cardiomyocyte extracellular matrix deposition. The effect of TRPV1 on improving myocardial fibrosis has been widely covered in previous studies. Activation of TRPV1 inhibits cardiac hypertrophy and fibrosis [42,43]. Wang et al. [115] found that TRPV1 activation attenuates the proliferation and differentiation of mouse fibroblasts induced by isoproterenol and prevents the development of myocardial fibrosis. In addition, long-term capsaicin intervention significantly improved myocardial hypertrophy and fibrosis in mice induced by high salt but did not improve in TRPV1- mice [43]. Similarly, continuous treatment of capsaicin reduced myocardial fibrosis in the hearts of diabetic mice but not in TRPV1- mice [80]. It can be seen that the benefits of TRPV1 in improving diabetic cardiac fibrosis is clear, but the specific mechanism remains to be studied.

Activate metabolic regulators and regulate cardiac energy metabolism

Impaired lipid metabolism is an important sign of diabetes, and is related to the occurrence of DCM [116]. The heart derives its main energy from fatty acids instead of glucose as its source. However, in diabetes, the proportion of fatty acid use is higher, on account of insulin resistance and reduced glucose intake [117]. Excessive fatty acid intake over the oxidation rate of the heart, results in an increase in the concentration of active lipids in cardiomyocytes and an increase in ROS production accrue to the β oxidation of concentrated lipids [116]. Several investigations have shown that changes in cardiomyocyte metabolism are of poverty touches of diabetic cardiac dysfunction [118–120]. Although the mechanism of the two remains unclear, it is mainly summarized by several factors, including disruption of calcium homeostasis, reduced cardiac efficiency, lipotoxicity, and myocardial mitochondrial damage. Capsaicin increases fat oxidation, prevents myocardial steatosis, and improves heart and liver function by regulating processes such as adipocyte browning and activating metabolic regulators, including AMPK, PPARα, glucagon-like peptide-1 (GLP-1) and uncoupling protein 1 (UCP1) [121]. These reactions of capsaicin are mediated by the excitation of TRPV1.

Regulating blood glucose and improving insulin sensitivity

TRPV1 receptor is expressed in rat islet β cells and β cell lines and affects insulin secretion [122]. This study also found that capsaicin dose-dependently increased insulin secretion in vitro, and this effect was suppressed by preconditioning with a TRPV1 antagonist. TRPV1 receptors also exist in the afferent sensory nerves innervating the islets. Therefore, TRPV1 activation may regulate insulin secretion directly by changing the secretion of β cells or indirectly by regulating sensory nerves [123]. Razavi et al. have put forward arguments that sensory neurons expressing TRPV1 master islet inflammation and insulin resistance [124]. Zhong et al. speculated that [125] TRPV1 mediates glucose-induced insulin secretion through the release of CGRP and SP. Other researchers have found that TRPV1 receptors exist in intestinal cells expressing GLP-1 and regulate glucose homeostasis and improve insulin sensitivity by inducing intestinal GLP-1 secretion [126,127]. TRPV1 activation regulates blood glucose homeostasis and even enhances insulin sensitivity in many ways.

Conclusion

Currently, hospitalization and mortality rates have significantly increased in patients with diabetes-related HF. Glycemic control effectively minimizes the possibility of HF in patients with diabetes [128]. For every 1% reduction in HbA1C, the risk of HF is reduced by 16% [129]. Table 2 summarizes the main effects of different types of hypoglycemic drugs on DCM and HF. Nevertheless, hypoglycemic therapy is ineffective in terms of cardiovascular endpoints [16]. Long-term blood glucose control cannot reverse cardiac structural remodeling and dysfunction. In some trials, it has not been proven that the hospitalization rate of HF in diabetic patients treated with antihyperglycemic drugs is lower [128]. Current guidelines for diagnosing and treating diabetes recommend a comprehensive approach to reduce the risk of diabetes-related complications. Special emphasis is placed on managing blood sugar, blood pressure and blood lipids, as well as lifestyle changes, as the basic elements to reduce and delay the cardiovascular risks associated with diabetes [130]. Another strategy to prevent DCM is reducing excessive fatty acid oxidation and lipotoxicity in the heart. Statins have been shown to reduce the incidence and mortality of coronary artery events in patients with diabetes with or without a history of cardiovascular disease [131]. SGLT2 inhibitors can reduce the accumulation of lipids in visceral fat and fat decomposition. The protective effect on myocardial lipotoxicity is not clear. Further research is needed to clarify this point.

Table 2. Summary of the main effects of different glucose-lowering agents on diabetic cardiomyopathy and heart failure.

Glucose-Lowering Agent	Mechanisms of Action	Impact on cardiovascular system
		MACE	Heart failure
Biguanides	↓ Liver glucose output ↓ Inflammation and oxidative stress ↓ cardiomyocytes and fibroblast LV remodeling ↑systolic and diastolic function	↓the occurrence of MACE	No significant effects on HF hospitalization
Sulfonylureas	↑ insulin secretion ↑ hypoglycemia risk ↑the risk of severe arrhythmia and myocardial ischemia	No significant effect on the occurrence of MACE	No significant effect on HF hospitalization
Thiazolidinediones	↓insulin resistance ↑water-sodium retention and edema	↓the occurrence of MACE	↑ risk of HF hospitalization
SGLT-2i	↑osmotic diuresis and natriuresis ↓edema and blood pressure ↓sodium-hydrogen exchanger ↑myocardial oxidation of glucose ↓myocardial fibrosis and remodeling ↑LV function ↓the activity of Sympathetic nervous system nerve fibers	↓the occurrence of MACE	↓risk of HF hospitalization and heart failure death
GLP-1RAs	↓blood pressure and blood lipids ↓cardiomyocyte apoptosis ↓vascular endothelial dysfunction ↑coronary blood flow ↓inflammatory pathways in cardiomyocytes ↓myocardial remodeling	↓the occurrence of MACE	↓risk of HF hospitalization
DPP-4i	↑the activity of Sympathetic nervous system nerve fibers ↑cardiomyocyte apoptosis ↑inflammation and oxidative stress ↓vascular endothelial dysfunction and atherosclerosis	No significant effect on the occurrence of MACE (↑ risk of on the occurrence of MACE only with saxagliptin)	No significant effect on HF hospitalization (↑ risk of HF hospitalization only with saxagliptin)

↑ stands for increase; ↓stands for reduction. MACE, major adverse cardiovascular events; HF, heart failure; SGLT-2i, Sodium-glucose cotransporter 2 inhibitors; GLP-1Ras, glucagon-like peptide-1 receptor agonist; DPP-4i, dipeptidyl peptidase-4 inhibitor.

Recently, GLP-1 agonists and SGLT2 inhibitors have been show to possess cardioprotective properties independent of the hypoglycemic pathway in patients with diabetes [132], as shown in Table 3. According to the 2023 American Diabetes Association (ADA) guidelines, regardless of baseline HbA1C levels, for patients with type 2 diabetes who have atherosclerotic heart disease or a high risk of cardiovascular disease or HF, SGLT2 inhibitors and/or GLP-1 agonists are recommended to reduce blood sugar and overall cardiovascular risk, including major cardiovascular adverse events and/or hospitalization risk for HF [130]. However, these two kinds of drugs also have many adverse reactions and limitations. Particularly, SGLT2 inhibitors cause an increased risk of urinary tract infection, lower limb amputation, diabetic ketoacidosis, fracture, and acute renal injury. GLP-1 agonists cause gastrointestinal reactions and an increased risk of pancreatitis and cholelithiasis. Moreover, since GLP-1 agonists is an injection drug, patient’s compliance is relatively poor. GLP-1 agonists and SGLT2 inhibitors offer new hope for preventing and treating diabetes. We speculate that TRPV1 analog also have a protective effect on the heart of diabetes. Further studies are required to clarify the potential targets and related mechanisms of TRPV1 channels in the heart of diabetes.

Table 3. Summary for the effects and adverse reactions of SGLT-2i and GLP-1Ras on diabetes heart.

	Drug	Dosage	Medianobservation period	Effects	Adverse reactions	References
Animal model
Human induced pluripotent stem cells exposed to 22mM glucose in 14 days	Empagliflozin	5 μM	10 minutes	↓Cardiomyocyte hypertrophy ↑Cardiomyocyte contractility ↓Myocardial dysfunction	Not applicable	Wu et al [133].
Streptozotocin‐induced diabetic rats	Exenatide	0.25 μg/kg (twice daily)	3 months	↓Oxidative stress ↓Cardiomyocyte apoptosis ↓Cardiac remodeling ↑Cardiac diastolic function	Not applicable	Wang et al [134].
High-fat diet-fed and STZ-treated rat model of T2DM	Liraglutide	50 or 100 or 500 μg/kg/day	8 weeks	↓ Cardiomyocyte apoptosis ↓ Myocardial endoplasmic reticulum stress ↑ Diastolic and systolic function independent of glycaemic control	Not applicable	Liu et al [135].
Diabetic mice by subcutaneous infusion of ATII for 30 days using an osmotic pump	Dapagliflozin	1.5 mg/kg/day	1 month	↓Inflammation ↓Myocardial fibrosis ↑Cardiac function	Not applicable	Arow et al [136].
Male Zucker diabetic fatty rats	Empagliflozin	10 or 30 mg/kg/day	6 weeks	↓Glucotoxicity ↓Oxidative stress in the aorta and in blood ↑Endothelial function	Not applicable	Sebastian et al [137].
High fat, high sucrose diet-induced diabetic cardiomyopathy mice	Ertugliflozin	0.5 mg/g/day	1 month	↓Mitochondrial dysfunction ↓Myocardial hypertrophy ↓Diastolic dysfunction ↑Contractile reserve ↓Energetic deficit	Not applicable	Dominiqueet al [138].
Clinical studies
T2DM patients with a high risk for cardiovascular events	Empagliflozin	10 mg/day or 25 mg/day	3.1 years	↓Primary composite cardiovascular outcome ↓Death from any cause	Genital infection	Bernard et al [139].
T2DM patients with a high risk for cardiovascular events	Canagliflozin	100 mg/day or 300 mg/day	188.2 weeks	↓Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke	A risk of amputation	Bruce et al [140].
T2DM patients who had or were at risk for atherosclerotic cardiovascular disease	Dapagliflozin	10 mg/day	4.2 years	→The occurrence of MACE ↓Cardiovascular death ↓Hospitalization for heart failure	Diabetic ketoacidosis	Stephen et al [141].
T2DM patients with at least one cardiovascular disease	liraglutide	1.8 mg (or the maxi- mum tolerat- ed dose) /day	3.8 years	↓Cardiovascular events ↓Death from any cause	Gastrointestinal reactions, acute gallstone disease	Steven et al [142].
Newly diagnosed and treatment-naive patients with T2DM	Liraglutide	1.8 mg/day	6 months	↓Arterial stiffness ↓Oxidative stress ↓NT-proBNP level ↑LV longitudinal myocardial strain and strain rate ↑LV twisting–untwisting ↑Endothelial function	Not mentioned	Viva et al [143].
T2DM patients without cardiovascular disease	Liraglutide	1.8 mg/day	26 weeks	↓LV diastolic filling and LV filling pressure ↓LV load	Gastrointestinal reactions	Maurice et al [35].

↑ stands for increase; ↓stands for reduction; →stands for no impact. SGLT-2i, Sodium-glucose cotransporter 2 inhibitors; GLP-1Ras, glucagon-like peptide-1 receptor agonist; STZ: streptozotocin; T2DM: type 2 diabetes mellitus; ATII: angiotensin II; MACE: major adverse cardiovascular events; NT-proBNP: N-terminal pro-B-type natriuretic peptide; LV: left ventricle.

In summary, based on current studies on patients with diabetes and animal experiments, activating TRPV1 can prevent the occurrence and development of diabetic organ dysfunction through a variety of different mechanisms, such as the inhibition of oxidative stress and inflammation, improvement of mitochondrial function, reduction of endothelial dysfunction and microvascular injury, and reduction of myocardial fibrosis and hypertrophy. However, Mandy et al. reported that 12 (S)-HETE, an effective TRPV1 activator, directly mediates endothelial calcium homeostasis disorders, mitochondrial lesions, and endothelium-dependent vasodilation in patients with diabetes [144]. They further pointed out that eliminating the 12 (S)-HETE/TRPV1 interaction in the TRPV1 Trp box could protect the function of diabetic vascular endothelial cells, increase left ventricular capillary density, and inhibit the worsening of HF with preserved ejection fraction caused by diabetes [145]. It seems that TRPV1 has complex effects under pathophysiological conditions, which could be the upshot of experimental differences. We speculate that different activators, antagonists, and gene knockout techniques may lead to differences in cardiovascular effects on TRPV1. The lipid peroxide 12 (S)-HETE is increased specifically in type 1 diabetic mice and humans and is also an endogenous activator of TRPV1. The plasma concentration of 12 (S)-HETE is particularly high in patients with type 1 diabetes diagnosed for the first time [146] and adult diabetic patients with vascular complications [147,148]. Most current studies use capsaicin to activate the TRPV1 channel to protect the heart from DCM; however, research on other TRPV1 activators or antagonists is not clear and developed enough, and the potency of TRPV1 analogues in the cure of cardiovascular disease is only just emerging. It is also believed that capsaicin has a biphasic effect on the vascular system: at lower concentrations, capsaicin (up to 10 nM) causes vasodilation in the skin due to sensory nerve activation, while higher concentrations (0.1–1 μ M) cause massive contraction in skeletal muscle arterioles due to non-neuronal TRPV1 stimulation [149]. It is not clear whether this difference is due to receptor sensitivity or the difference in TRPV1 receptor density between the two tissues. Further research is needed to clarify the potential targets and related mechanisms of TRPV1 channels in the diabetic heart, to provide medicine professionals unique TRPV1 agonists to prevent and treat diabetes-related cardiovascular diseases.

Thus far, no consensus has been reached on the optimal management strategy for preventing or treating of diabetes-related cardiovascular complications. Current published studies have confirmed the latent protective roles of TRPV1 against atherosclerosis, cardiac ischemic stress, and pathological hypertrophy. Considering that TRPV1 may also have a unique cardioprotective effect in diabetic models, this study summarized the benefits of the TRPV1 channel on blood glucose and cardiovascular diseases in diabetic models. We hope to aid in the diagnosis, prevention, and treatment of cardiovascular diseases in patients with diabetes.

Disclosure statement

The authors do not declare any conflict of interest relevant to this manuscript.

Data availability statement

No data are available for this review.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China under Grant No. 81670447; the Zhejiang Provincial Health Commission Project under Grant No. 2017KY559. LW is sponsored by Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.