Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius for his discovery of capsaicin receptors in 1997.[1] The capsaicin receptor is also called transient receptor potential vanilloid subfamily member 1 (TRPV1) and belongs to the transient receptor potential channels family. TRPV1 possesses a tetrameric structure consisting of 6 transmembrane regions, a pore-shaped region between the fifth (S5) and sixth transmembrane regions (S6), a cytoplasmic amino group, and a carboxyl terminus, which is selectively permeable for cations such as H+, Na+, and Ca2+.[1] TRPV1 can be activated by nociceptive thermal stimulation (temperature > 43°C), pH values less than 5.96, and capsaicin, a pungent component of chili peppers, and other factors including free oxygen radicals, 12-lipoxygenase, 20-hydroxyeicosatetraenoic acid, etc. Activation of TRPV1-induced neuronal depolarization transmitted to the central nervous system creates thermal and pain sensations.[2] In addition, activation of TRPV1 can also promote the release of calcitonin gene-related peptide (CGRP), substance P (SP), and other neurotransmitters.[3,4] The discovery of TRPV1 has increased our understanding of how temperature triggers nerve impulses, because our ability to perceive ambient temperature is essential for survival and the basis of our interaction with the world around us. This perspective focuses on the actions of TRPV1 in the regulation of cardiometabolic function and beneficial effects of spicy food on the prevention of cardiometabolic diseases. TRPV1 and regulation of cardiometabolic function TRPV1 is distributed not only in the nervous system, but also in non-neuronal tissues and organs such as the heart, liver, pancreas, vasculature, kidney, intestine, skeletal muscle, and fat tissues.[2] In addition to sensing temperature, TRPV1 may impact cardiometabolic function. In 2004, our team began to focus on the role of TRPV1 in the regulation of cardiometabolic function and its relevance to cardiometabolic diseases because epidemiological data in China revealed a remarkable difference in the prevalence of cardiometabolic diseases between subjects who prefer spicier food and those who prefer less spicy food. Role of TRPV1 in vascular function and heart function The TRPV1 channel is expressed in myocardium, epicardial surface, vascular endothelial cells, vascular smooth muscle cells (VSMCs), and peripheral sensory nerves of the heart.[4,5] Activation of endothelial TRPV1 by capsaicin relaxes blood vessels by modulating the potassium channel and the Ca2+ dependent potassium channel.[6] Our study showed that activation of endothelial TRPV1 by capsaicin promotes Ca2+ influx, which increases the phosphorylation of protein kinase A (PKA) and endothelial nitric oxide synthase (eNOS), thereby promoting nitric oxide (NO) production in endothelial cells.[7] Activation of TRPV1 also increases the intracellular calcium level and promotes the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, which affects VSMC proliferation and migration.[8] Activation of TRPV1 in perivascular sensory neurons can promote the release of CGRP, SP, and other neuropeptides, thus leading to vasodilatation.[5] TRPV1 in afferent neuronal baroreceptors maintains blood pressure homeostasis.[9] TRPV1 expressed in cardiac nodes and sympathetic afferent fibers, cardiomyocytes, and fibroblasts affects cardiac structure and function.[10] After coronary artery ligation in TRPV1 knockout mice, the cardiac infarction area, inflammatory cell infiltration, capillary density, and collagen content of myocardium as well as mortality significantly increased.[8] Knockout of TRPV1 in mice increased the expression of transforming growth factor-β1, Smad2, vascular endothelial growth factor, and matrix metalloproteinase 2 (MMP2) in myocardium and promoted cardiac fibrosis as well as reduced the production of CGRP and SP.[10] Role of TRPV1 in metabolic regulation TRPV1 has been detected in several key metabolic organs, but its roles in these organs remain elusive. We reported the expression of TRPV1 in adipocytes and white adipose tissue. Activation of TRPV1 by capsaicin can increase adipocyte calcium levels and reduce triglyceride production through inhibition of peroxisome proliferator-activated receptor γ (PPAR γ) and fatty acid synthase.[11] Reduction off at accumulation by TRPV1 activation is also associated with an increased gap junction protein 43 (Cx43)-mediated Ca2+ influx.[12] The expression of TRPV1 is rich in brown fat. TRPV1 activation by capsaicin promoted sirtuin-1 (SIRT-1) expression and its acetylation as well as the interaction between PPAR γ and PR/SET Domain-16 (PRDM-16).[13] TRPV1 also regulates the glucose homeostasis through several pathways. Capsaicin can increase insulin secretion in a dose-dependent manner via TRPV1 in rodent islet β cells and β cell lines.[14] TRPV1 regulates insulin secretion by stimulating the afferent sensory nerves that innervate islet cells.[14] TRPV1 has also been localized in secretion tumor cell-1 (STC-1) cells and ileum.[15] TRPV1 activation by capsaicin stimulated glucagon-like peptide-1 (GLP-1) secretion from STC-1 cells in a calcium-dependent manner and also increased GLP-1 and insulin secretion, thus improving glucose tolerance.[15] Hepatic TRPV1 activation by capsaicin reduced lipid accumulation in the liver[16] and up-regulated the expression of uncoupling protein 2 (UCP2) and PPAR δ to prevent fatty liver.[17] TRPV1 in skeletal muscle is associated with more mitochondrial biogenesis, oxidative fiber production, and enhanced exercise endurance.[18] In addition, activation of TRPV1 also increased AMPK expression and promoted glucose oxidation and ATP production in skeletal muscle.[19] TRPV1 dysfunction and cardiometabolic diseases Dysfunction of TRPV1 is associated with pathogenesis of cardiometabolic diseases. Lower TRPV1 expression in visceral adipose tissue from obese mice and obese humans was accompanied by reduced capsaicin-induced calcium influx.[11] Capsaicin treatment prevented high-fat diet-induced obesity in mice by increasing lipolysis via Cx43-mediated Ca2+ influx that enhanced the expression of phospho-calmodulin (p-CaM), calmodulin-dependent protein kinase II (CaMK II), PPAR δ, and hormone sensitive lipase (HSL) in adipose tissues.[11,12] The inhibitory effect of capsaicin on obesity-related brown adipose tissue (BAT) whitening was mediated by SIRT3 that prevented mitochondrial calcium overload.[20] The low expression of TRPV1 in BAT caused glucose intolerance and hypercholesterolemia and decreased the plasma GLP-1 level; in contrast, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in plasma and ileum.[15] In diabetic mice, hyperglycemia decreased TRPV1 expression and PKA phosphorylation in endothelial cells, which was reversed by capsaicin in a UCP2-dependent manner.[21] In addition, activation of TRPV1 potently improved diabetic nephropathy by inhibition of hyperglycemia-induced mitochondrial dysfunction in podocytes.[22] Also, TRPV1 prevented the development of fatty liver through stimulating lipolysis by increasing UCP2, phosphorylated HSL, carnitine palmitoyl transferase 1, and PPAR δ.[17] In skeletal muscle, TRPV1 activation promoted mitochondrial biogenesis, increased oxidative fibers, and enhanced exercise endurance.[18] In addition to ameliorating metabolic disorders, TRPV1 activation also benefits cardiovascular diseases (CVDs). Long-term stimulation of TRPV1 by dietary capsaicin activates PKA that increases NO synthase phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats.[7] Activation of TRPV1 in mesenteric arteries also reduces high-salt-diet-induced endothelial dysfunction and nocturnal hypertension by restoring NO production.[23] In the kidneys, TRPV1 activation promoted urinary sodium excretion by inhibiting epithelial sodium channel α subunit-mediated sodium reabsorption.[24] Activation of TRPV1 by dietary capsaicin mediated increases in phosphorylation of eNOS delayed the onset of stroke and increased the survival time in stroke-prone spontaneously hypertensive rats.[25] In addition, activation of TRPV1 also increased the ATP-binding cassette transporter A1 and reduced low-density lipoprotein (LDL) receptor-related protein 1 expression in the aorta, thus inhibiting atherosclerotic lesions by reducing foam cell formation from VSMCs.[26] The upregulation of PKA/UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction.[27] In the heart, activation of TRPV1 by capsaicin attenuated high-salt-diet-induced cardiac hypertrophy and fibrosis by restoring mitochondrial complex I oxidative phosphorylation and sirtuin 3 expression.[28,29] Spicy food consumption and prevention of cardiometabolic diseases TRPV1 agonists and antagonists are mainly used for analgesia, and their side effects include temperature changes, among others.[30] The protective effect of TRPV1 in cardiometabolic disease is mainly based on the population observation of spicy food intake. Capsaicin is a major pungent component of chili peppers and can specifically activate TRPV1.[2] Currently, the Dietary Approaches to Stop Hypertension diet in the United States and Mediterranean Diet in the Europe are recommended as dietary therapies for the prevention of cardiometabolic diseases.[31] Although basic studies have provided a large amount of evidence that dietary capsaicin-activating TRPV1 can ameliorate the pathogenesis of cardiometabolic diseases [Figure 1], it remains unclear whether spicy food is beneficial in clinical studies.[32]Figure 1: Roles of TRPV1 and spicy food in the amelioration of cardiometabolic diseases. ABCA1: ATP-binding cassette transporter A1; ARD: Ankyrin repeating domain; eNaC: Epithelial sodium channel; eNOS: Endothelial nitric oxide synthase; FAS: Fatty acid synthase; GLP-1: Glucagon-like peptide 1; LRP1: Low-density lipoprotein receptor-related protein 1; NO: Nitric oxide; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator 1 α; PKA: Protein kinase A; PPAR δ: Peroxisome proliferator-activated receptor δ; PPAR γ: Peroxisome proliferator-activated receptor γ; ROS: Reactive oxygen species; TRP: Transient receptor potential domain; TRPV1: Transient receptor potential vanilloid subfamily member 1; UCP2: Uncoupling protein 2.Effect of spicy food on blood pressure A systematic review and meta-analysis of randomized controlled trials showed that supplementation with fermented red pepper paste (FRPP) improved systolic blood pressure and diastolic blood pressure.[33] Nine years of data from the China Health and Nutrition Survey (CHNS) showed that chili intake is inversely associated with the risk of developing hypertension in Chinese adults aged 20 to 75 years.[34] The China Kadoorie Biobank (CKB) prospective study and CHNS showed that frequency of spicy food consumption was inversely associated with risk of hypertension in females but not males.[35,36] We also reported that consuming spicy foods significantly reduced individual salt preference, daily salt intake, and blood pressure by modifying the neural processing of salty taste in the brain.[37] Use of spicy flavors may be a promising behavioral intervention for reducing high salt intake and blood pressure. Effect of spicy food on glycolipids and obesity In 1549 participants aged 65 years in the CHNS, the frequency and the average amount of spicy food intake were both inversely associated with LDL-cholesterol and LDL-cholesterol:HDL-cholesterol ratio after adjustment for potential confounders and cluster effects.[38] A 4-week intervention with chili peppers, equivalent to 5 mg/day capsaicin, successfully improved fasting blood lipid profiles compared with placebo in women with gestational diabetes mellitus (GDM).[39] Consumption of 30 g/day chopped chili peppers for 4 weeks also increased the resistance of serum LDL to oxidation in healthy subjects.[40] A clinical trial conducted in 28 females for 12 weeks revealed that treatment with FRPP evoked a greater cholesterol-modulating effect.[41] The consumption of chili peppers has a potential immediate thermogenic effect and a potential hypoglycemic effect in sedentary people.[42] Capsaicin-containing chili supplementation regularly improved postprandial hyperglycemia and hyperinsulinemia as well as decreased the incidence of large-for-gestational-age newborns in women with GDM.[39] The CKB prospective study showed that spicy food consumption was inversely associated with the risks of death due to diabetes in the whole cohort after multivariate adjustment.[43] A large-scale longitudinal, household based survey in China showed that subjects without chili intake had higher insulin resistance compared with subjects with chili intake.[44] In healthy individuals, taking capsicum capsules lowered plasma glucose levels and increased plasma insulin levels.[39] In a randomized, double-blind, placebo-controlled, 8-week trial with a combination of nutrients including capsaicin, there was a decrease in insulin resistance and inflammatory adipokines.[45] Epidemiological data revealed that the consumption of foods containing capsaicin was associated with a lower prevalence of obesity. The CKB study recruited a total of 434,556 adults aged 30 to 79 years. It showed that the prevalence of daily intake of spicy food rate was dramatically geographically diverse. In areas with increased frequency, intensity and duration of spicy food consumption, the obesity parameters decreased significantly after covariate adjustment.[46] Another double-blind, randomized, placebo-controlled trial indicated that treatment of overweight or obese subjects with capsinoid for 12 weeks reduced abdominal fat.[47] In moderately overweight subjects, 12-week administration of noninvamide, a non-pungent capsaicin analogue, prevented diet-induced systemic fat gain.[48] Capsaicin treatment caused sustained fat oxidation during weight maintenance compared with placebo.[49] A randomized double-blind study showed that subjects treated with capsinoid for 4 weeks increased their oxygen consumption and resting energy expenditure.[50] Effect of spicy food on fatty liver and muscle endurance Dietary factors including spicy foods were associated with fatty liver in an Indian study.[51] The occurrence of fatty liver was inversely associated with frequent consumption of spicy foods in a cross-sectional study including 9378 participants in China.[52] A population-based cross-sectional study found a positive correlation between frequency of chili consumption and muscle strength in adult males.[53] Healthy young men taking capsaicin analog supplementation produced higher maximal isometric force and delayed fatigue compared to those taking placebo.[54] Spicy food consumption and CVD risk The CKB study revealed that spicy food consumption was inversely associated with the risks of death due to ischemic heart diseases in the whole cohort after multivariate adjustment.[43] In the Molisani cohort study, regular consumption of chili pepper was associated with decreased risk of ischemic heart disease (hazard ratio (HR): 0.56; 95% confidence interval (CI): 0.35–0.87) and cerebrovascular death (HR: 0.39; 95% CI: 0.20–0.75).[55] A meta-analysis of 4 studies (from the United States, China, Italy, and Iran) that recruited more than a half million participants showed that spicy food consumption was associated with significant reduction of total mortality and CVD death risk.[56] In conclusion, a consumption of spicy food recommendation has been written into China's guidelines for prevention of cardiometabolic diseases through a healthy lifestyle.[57,58] If more prospective and randomized clinical trials can further validate the cardiometabolic benefits of spicy food, it would be a low-cost, widespread, and easy to implement dietary therapy to prevent cardiometabolic diseases. The discovery of TRPV1 not only illuminates the principle of temperature and pain perception but also provides a promising strategy for the prevention of cardiometabolic diseases in the population. Funding This work was supported by grants from the National Basic Research Program of China (2006CB503905) and the National Natural Science Foundation of China (81721001, 31701023, 81900380). Conflicts of interest None.