Chapter 18 Zhiming Zhu*; Daoyan Liu; Shiqiang Xiong Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China Hypertension, obesity, and diabetes severely affect human health and result in metabolic disturbance-induced vascular lesions. Mounting evidence indicates that a new family of nonselective cation channels, called transient receptor potential (TRP) channels, plays an important role in the regulation of vascular function and metabolism. The functional equilibrium between TRP channels is critical for maintenance of vascular physiological function and blood pressure. Imbalance of TRP channel function may be one etiology of hypertension. In addition, changes in expression or dysfunction of TRP channels likely result in the development of metabolic syndrome. It is of great interest to further elucidate how TRP channels are involved in the physiology and pathology of vascular function and metabolism. Furthermore, it should accelerate translational research in TRP channels and, in particular, promote novel research findings from bench to bedside. Hypertension, traditionally defined as a condition associated with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, affects 1 billion people worldwide [1,2]. As one of the leading risk factors for deadly cardiovascular disease, hypertension is emerging as an important global public-health challenge. The pathogenesis of hypertension is complex, involving both genetic and environmental factors. Hypertension has been traditionally thought to be due to neural and humoral stimulation of vascular constriction and to endocrine and renal stimuli that control blood volume. Of these stimuli, intracellular Ca2 + homeostasis is essential for vascular function and blood pressure regulation [3]. Dysregulation and disturbance of Ca2 + homeostasis has been noted in experimental and human hypertension [4,5]. Although increased transmembrane calcium influx and enhanced calcium release via store-operated calcium (SOC) entry or receptor-operated calcium (ROC) entry have been observed in the vasculature of hypertensive rats, the mechanism underlying the abnormal cellular calcium handling remains to be elucidated. During the past two decades of research in vascular function regulation, a family of nonselective cation channels, called transient receptor potential (TRP) channels, has received attention because these channels play a unique role in regulating intracellular Ca2 + concentration and vascular function [6]. Mounting evidence indicates that TRP channels participate in vascular dysfunction and the development of hypertension. It has been reported that all transient receptor potential canonical (TRPC) channel isoforms are expressed in endothelial cells [7]. Transient receptor potential melastatin 4 (TRPM4) and transient receptor potential vanilloid 4 (TRPV4) are also present in vascular endothelial cells, although they appear less abundant. All the TRP channels (except TRPV5, TRPV6, and TRPM1) are reportedly present in arterial smooth muscle from various segments of the vasculature [8]. Several TRP channels contribute to the contraction of blood vessels. Overexpression of the human TRPC1 gene in rat pulmonary artery enhances vasoconstriction via store depletion-mediated Ca2 + influx [9]. Thapsigargin-stimulated store-operated current was reduced in both TRPC1 siRNA- and TRPC1 antisense-expressing cells [10]. These findings suggest that TRPC1 is a component of the store-operated Ca2 + entry pathway. TRPC3 is involved in Uridine Triphosphate (UTP)-mediated depolarization and vasoconstriction of both coronary and cerebrovascular smooth muscle cells (SMCs) [11]. TRPC6 is implicated in pressure-induced depolarization and vasoconstriction and contributes to myogenic constriction of cerebral arteries [12]. Dietrich et al. showed that constitutively active TRPC3 channels were up-regulated in TRPC6-deficient SMCs and that vascular SMC contractility was increased [13]. TRPC6 channels are thought to play a fundamental role in the regulation of smooth muscle tone in blood vessels [14]. Kark et al. demonstrated that functional expression of TRPV1 in vascular SMCs mediated vasoconstriction of the resistance arteries [15]. TRPM4 was discovered to contribute to pressure-induced SMC depolarization and vasoconstriction [16] and cerebral blood flow regulation [17]. In contrast, some TRP channels are involved in vasodilation. TRPC1/TRPC3 is inhibited by the NO/cyclic guanosine monophosphate/Protein Kinase G (cGMP/PKG) pathway in SMCs and contributes to NO-induced vasorelaxation [18]. An essential role for TRPC4 channels in endothelium-dependent regulation of vascular tone has been recently proposed [19]. Agonist-induced Ca2 + entry is dramatically reduced in aortic endothelial cells of mice that lack TRPC4; the endothelium-dependent vascular relaxation in response to ATP and acetylcholine is also impaired [19]. TRPV1 is expressed abundantly in the endothelium. In isolated rat and mouse mesenteric arteries, activation of TPRV1 by its agonist capsaicin elicits an acute release of NO from endothelial cells and leads to vasodilation [20]. In contrast, this effect is reduced by TRPV1 receptor antagonists and is absent in arteries of the TRPV1−/− mouse [20]. TRPV4 is also involved in vasodilation induced by epoxyeicosatrienoic acid compounds [21], which cause endothelium-dependent vasodilation in rat coronary and cerebral arteries [22,23]. Both endothelial and smooth muscle TRPV4 channels are critical for vasodilation of mesenteric arteries in response to endothelial-derived factors [24]. Earley et al. reported that TRPA1 channels were present in the endothelium of rat cerebral and cerebellar pial arteries [25]. Activation of TRPA1 channels causes endothelium-dependent SMC hyperpolarization and vasodilation in this vascular bed [25]. Abnormal expression and function of TRPC channels have been reported in both essential hypertension patients and rat models. Thilo et al. observed a significant correlation between TRPC3 transcripts and systolic blood pressure, expression of IL-1β, and TNF-α in monocytes from patients with essential hypertension [26]. They observed an approximately eightfold increase in TRPC3 transcripts in monocytes from patients with essential hypertension compared with normotensive control subjects [26]. Liu et al. compared the expression level and function of TRPCs between essential hypertensive patients and normotensive control subjects, and for the first time, they noted increased TRPC3 and TRPC5 protein expression and an increase in the gadolinium/calcium-influx ratio in essential hypertensive patients via TRPCs [27]. In addition, increased TRPC3 and TRPC5 expression and a subsequent SOC influx and increased 1-oleoyl-2-acetyl-sn-glycerol-induced cation influx in monocytes of patients with essential hypertension were observed ([28]; Table 18.1). Table 18.1 Roles of TRP Channels in the Regulation of Vascular Function and the Pathogenesis of Hypertension For details and references, see text. Mutations in the gene encoding WNK lysine deficient protein kinase 4 (WNK4), which is a WNK family kinase that regulates the expression of TRPV4, have been linked to monogenic hypertension. Fu et al. reported that coexpression of WNK4 down-regulated TRPV4 function by decreasing its cell surface expression in HEK-293 cells [39]. They demonstrated functional regulation of TRPV4 by WNK4 and speculated that this pathway may influence systemic Ca2 + balance [39]. Disturbances in the regulation of the cytosolic calcium concentration play a key role in the pathogenesis of primary hypertension. Liu et al. evaluated the expression and function of calcium-permeable TRPCs in normotensive WKY and spontaneously hypertensive rats (SHRs) and demonstrated an increase in TRPC3 channel expression, increased TRPC3-related calcium influx, which was associated with increased contraction, and an increase in angiotensin II-induced TRPC3 expression in vasculature from SHRs [5,39]. Furthermore, they noted that increased rhythmicity in hypertensive arterial smooth muscle is linked to TRPCs [29]. Norepinephrine-induced vasomotion and calcium influx were increased in mesenteric arterioles from SHRs, and TRPC1, TRPC3, and TRPC5 expression was also up-regulated [29]. Administration of candesartan or telmisartan, but not amlodipine, significantly reduced the expression of TRPC1, TRPC3, and TRPC5 and norepinephrine-induced vasomotion in mesenteric arterioles from SHRs [29]. In addition, TRPC3 channel expression was greatly enhanced in TRPC6 knockout mice; however, up-regulation of TRPC3 did not functionally replace TRPC6 [13]. TRPC6 knockout mice show increased blood pressure and enhanced agonist-induced arterial vasoconstriction [13]. Increased TRPC3 expression relative to that of TRPC6 may predispose mice to hypertension [40]. Bae et al. reported that expression of TRPC6 and ROC currents were increased in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats [41]. The presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension (PH) in the mouse model [42]. Chronic hypoxia increased serotonin-induced vasoconstriction significantly; the augmented vasoreactivity was attenuated in TRPC1−/− and eliminated in TRPC6−/− pulmonary arteries [42]. Intracellular Mg2 + depletion has been implicated in vascular dysfunction in hypertension. Reduced TRPM7 expression is associated with reduced cytosolic Mg2 + concentration in mesenteric arterial SMCs from SHRs, which may facilitate vasoconstriction [36]. TRPM8 is involved in the regulation of vascular tone [37]. Liu et al. reported that down-regulation of TRPM8 may contribute to the enhanced vasoreactivity in PH [38]. Emerging evidence has shown that the TRPV1 channel is implicated in hypertension. TRPV1 activation exerts antihypertension effects by stimulating the release of calcitonin gene-related peptide (CGRP) from capsaicin-sensitive nerves and NO from endothelial cells [30]. Plasma concentrations of CGRP rise transiently after acute administration of capsaicin in adult rats and is accompanied by a decrease in blood pressure [31]. Our study demonstrated that activation of TRPV1 increased the phosphorylation of Protein Kinase A (PKA) and endothelial nitric oxide synthase (eNOS) and, thus, the production of NO in endothelial cells. Long-term stimulation of TRPV1 by dietary capsaicin lowered blood pressure in SHRs, but there was no change in plasma concentration of CGRP and substance P in SHR after long-term consumption of capsaicin [20]. TRPV1 has also been proposed to be involved in the pathogenesis of salt-induced hypertension. Wang demonstrated that TRPV1 was activated and its expression was up-regulated during high salt intake in Dahl salt-resistant rats, which prevented the salt-induced increase in blood pressure [32]. In contrast, TRPV1 expression and function was impaired in Dahl salt-sensitive rats, which rendered Dahl salt-sensitive rats to salt load in terms of blood pressure regulation [32]. Our study revealed that chronic administration of capsaicin reduced the high-salt-intake-induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and via NO reduction in mesenteric arteries by activating vascular TRPV1 [33]. TRPV1 receptors may also mediate a general aversive response to salt [34], indicating a role for TRPV1 in regulating salt intake behaviors that are linked to the development of salt-sensitive hypertension. TRPV4 channels are also critically associated with salt-sensitive hypertension. Salt intake may enhance the expression of TRPV4 to counterbalance salt-induced increases in blood pressure in a salt-resistant strain of rats [35]. These findings highlight a promising role for TRPV4 in the treatment of salt-sensitive hypertension [35]. High blood pressure frequently causes target organ damage including atherosclerosis, cardiac hypertrophy, stroke, myocardial infarction, and end-stage renal failure [43]. Recent studies have shown that some TRP channels participate in the pathogenesis of cerebrovascular dysfunction, cardiac hypertrophy, renal damage, and atherosclerosis. TRPC3 channels play a fundamental role in the regulation of vascular smooth muscle tone and in autoregulation of cerebral blood flow due to their role in the regulation of cerebral vascular contractility [44]. Suppression of TRPC3 expression in arterial vascular smooth muscle significantly decreased the depolarization and constriction of intact cerebral arteries in response to UTP [11]. In isolated cerebral artery myocytes, SR Ca2 + release, IP3-induced [Ca2 +]i elevation, and vasoconstriction were reduced after TRPC3 knockdown and treatment with voltage-dependent Ca2 + channel blockers [45]. Thilo et al. proposed that TRPC3 expression was associated with hypertension and hypoxic conditions in human cerebral vascular tissue [46]. Reading and Brayden suggested that TRPM4 channels in cerebrovascular myocytes contributed to the autoregulation of cerebral blood flow in vivo [17]. In vivo suppression of TRPM4 decreased cerebral artery myogenic constriction and impaired autoregulation [17]. Gerzanich et al. showed a role for TRPM4 in secondary hemorrhage following central nervous system injury [47]. The up-regulation of TRPM4 led to cellular swelling and oncotic cell death [47]. TRPM6 was significantly reduced in cerebral vascular tissue taken from patients after hypertensive intracerebral hemorrhage when compared with control tissue [46]. Xu et al. demonstrated that activation of TRPV1 channels by dietary capsaicin caused increased phosphorylation of eNOS, delayed the onset of stroke, and further increased survival time in stroke-prone SHRs [48]. Hypertension plays an important role in the development of cardiac hypertrophy and heart failure. Emerging evidence indicates that TRP channels are critical regulators of microdomain signaling in the heart that controls pathological hypertrophy together with signaling via effectors including calcineurin and nuclear factor of activated T cells (NFAT) [49]. Ohba et al. first reported a potential role for TRPC1 channels in pressure overload-induced hypertrophy [50]. Expression of TRPC1 was significantly increased in the hearts of abdominal aortic-banded rats compared with sham-operated rats. ET-1 treatment resulted in increased expression of brain natriuretic protein, atrial natriuretic factor, and TRPC1 and increased cell surface area in neonatal myocytes. Silencing of TRPC1 with siRNA attenuated store-operated calcium entry (SOCE) and cardiac hypertrophy. TRPC1 gene-deleted mice were profoundly protected from cardiac hypertrophy following pressure overload [51]. NFAT is a Ca2 +-dependent transcription factor that is activated in pathological hypertrophy [52]. Several subtypes of TRPC mediate Ca2 + influx, which is essential for NFAT-mediated hypertrophy. Nakayama et al. demonstrated that TRPC3-overexpressing transgenic mice showed significant increases in SOCE and developed cardiomyopathy with a loss of ventricular functional performance [53]. In addition, cardiac hypertrophy was synergistically increased in TRPC3 transgenic mice when they were subjected to pressure overload or Ang II phenylephrine infusion [53]. However, the augmented hypertrophic phenotype in TRPC3 transgenic mice was abolished when calcineurin Aβ was deleted [53]. Selective inhibition of TRPC3 via Pyr3 was reported to attenuate activation of NFAT and block cardiac hypertrophy in mice subjected to pressure overload [54]. Similarly, studies from other groups showed that cardiac-specific TRPC6 transgenic mice showed heightened sensitivity to pressure overload and agonist-induced cardiac hypertrophy [55]. TRPC6 acts as a positive regulator of calcineurin-NFAT signaling that drives pathological hypertrophy [55]. Recently, Wu et al. generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 that block the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart [56]. Remarkably, all three dn transgenic strategies attenuated the cardiac hypertrophic response following either neuroendocrine agonist infusion or press-overload treatment. In addition, dnTRPC4 cross-inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that TRPC subfamilies function as a coordinated complex [56]. The prohypertrophic effects of TRPC channels have also been shown in vitro in cultured cardiomyocytes [49]. The expression of TRPM4 protein is increased in cardiomyocytes from SHRs and is associated with left ventricular hypertrophy relative to normotensive WKY rats [57]. The kidney is one of the major target organs for hypertension, which regulates blood pressure via sodium excretion [37]. TRP channels expressed along different parts of the nephron suggest their involvement in renal function and/or pathogenesis of renal diseases [58]. TRPC6 channels have been proposed to influence the filtration barrier function of podocytes in the glomerulus [59]. Transient overexpression of TRPC6 in the mice slit diaphragm resulted in proteinuria [59]. This abnormally high expression led to disturbed Ca2 + regulation and disruption of the podocyte actin cytoskeleton, which in turn led to impaired podocyte function and proteinuria [59]. Thilo et al. demonstrated that VEGF regulated TRPC6 expression in podocytes and proteinuria [60]. Activation of TRPV1 in vivo or in isolated perfused kidneys increased the glomerular filtration rate and enhanced renal sodium and water excretion [61,62]. TRPV1 dysfunction led to impaired renal excretory function and disturbed hemodynamic homoeostasis [63]. A protective role of TRPV1 was observed in uninephrectomized mice administered with Deoxycortone Acetate (DOCA)-salt [64]..Renal inflammation was aggravated in TRPV1 knockout mice subjected to DOCA-salt hypertension [65]. These findings imply that TRPV1 mediates a protective signal pathway in salt-induced renal damage. Disturbance of the intracellular Mg2 + concentration leads to vascular dysfunction in hypertension [36]. TRPM6 is crucial for transcellular Mg2 + transport in the kidney. Loss-of-function mutations in TRPM6 lead to hypomagnesemia with secondary hypocalcemia [66]. TRPV4 may function as an osmoreceptor in the kidney and participate in the regulation of sodium and water balance [67]. These TRP channels may play a role in hypertension by regulating the total body divalent cation homeostasis and renal perfusion/hemodynamics. Mounting evidence reveals a critical role of TRP channels in the physiological regulation of vascular function and blood pressure. Functional equilibrium between TRP channels plays a critical role in maintaining vascular physiological function and blood pressure. Enhanced TRPC3/5-mediated vasoconstriction and impaired TRPV1-induced vasodilation was detected in hypertension [5,20,29,68,69]. Based on these findings, we propose that the imbalance in TRP channel function may be one etiology of hypertension. The impaired balance in TRP channel function results in elevated [Ca2 +]i and enhanced vasoconstriction and/or reduced vasodilation, thus contributing to the development of hypertension (Figure 18.1).
Transient Receptor Potential Channels in Hypertension and Metabolic Syndrome
* Corresponding author: zhuzm@yahoo.com
Abstract
TRP Channels in Hypertension
Introduction
Distribution of TRP Channels in the Vasculature
TRP Channels Participate in the Regulation of Vascular Function
TRP Channels in the Pathogenesis of Hypertension
TRP Channels Implicated in Human Hypertension
TRP channels
Distribution
Proposed roles
Main References
TRPC1
TRPC1, TRPC3
VSMC
VSMC
A component of store-operated Ca2 + entry pathway.
1. Inhibited by the NO/cGMP/PKG pathway in VSMC, contributes to NO-induced vasodilation
2. Increased expression and contribution to increased vasomotion in hypertension
[9,10]
[18]
[29]
TRPC3
VSMC
Involved in UTP-mediated depolarization and vasoconstriction
[11]
TRPC3, TRPC5
VSMC
Monocyte
Increased expression and calcium influx in VSMC and monocytes from hypertensive animals and patients
[27,28]
TRPC6
VSMC
TRPC6 knockout mice show elevated blood pressure and enhanced vasoconstriction
[13]
TRPV1
VSMC
Endothelial cell
1. Expressed in VSMC and mediating vasoconstriction of the resistance arteries
2. Involved in endothelial-dependent vasodilation
3. TRPV1 activation prevents hypertension
4. TRPV1 reduction is related to salt-induced increase in blood pressure
5. Regulation of salt-intake behaviors that are associated with the development of salt-sensitive hypertension
[15,20,30–34]
TRPV4
VSMC
Endothelial cell
1. TRPV4 activation in the endothelium and VSMC promotes the vasodilation of mesenteric arteries
2. Enhanced expression of TRPV4 may counterbalance salt-induced increases in blood pressure
[24,35]
TRPM4
VSMC
Contribution to pressure-induced vasoconstriction and cerebral blood flow regulation
[16,17]
TRPM7
VSMC
Reduced TRPM7 in SHRs contributes to vasoconstriction in VSMC
[36]
TRPM8
VSMC
1. Regulation of vascular tone
2. Reduced TRPM8 may contribute to the enhanced vasoreactivity in PH
[37,38]
TRPA1
VSMC
Endothelial cell
TRPA1 activation elicits cerebral artery vasodilation
[25]
TRP Channels in Hypertensive Animal Models
Dysfunction of TRP Channels is Associated with Hypertension-Related Target Organ Damage
TRP Channels in Cerebrovascular Dysfunction
TRP Channels and Cardiac Hypertrophy
TRP Channels in Renal Dysfunction
Summary
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Transient Receptor Potential Channels in Hypertension and Metabolic Syndrome
Figure 18.1 The functional balance in TRP channels in the regulation of vascular function and blood pressure. Multiple TRP channels are present in VSMC and the endothelium. Activation of TRPC3/5 results in an increase in VSMC [Ca2 +]i via SOC- and diacylgylcerol (DAG)-mediated Ca2 + influx. Ang II and norepinephrine upregulate TRPC3/5 expression and lead to consequent Ca2 + influx and vasoconstriction. Activation of TRPV1 increases the phosphorylation of PKA and eNOS, thereby leading to production of NO in endothelial cells and vasodilation. A disturbance to this balance leads eventually to hypertension.
