TRPC channels: Dysregulation and Ca2+ Mishandling In Ischemic Heart Disease (original) (raw)
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TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling
Frontiers in Physiology
Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart's structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca 2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca 2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.
Proceedings of the National Academy of Sciences of the United States of America, 2017
The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase. Working in vitro with H9c2 cardiomyoblasts subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and analyzing changes occurring in areas-at-risk (AARs) of murine hearts subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) protocol, we found: (i) that blocking TRPC with SKF96365 significantly ameliorated damage induced by H/R, including development of the mitochondrial permeability transition and proapoptotic changes in Bcl2/BAX rat...
TRPC1 Channels Are Critical for Hypertrophic Signaling in the Heart
Circulation Research, 2009
Rationale: Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein-coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes. Objective: Transient receptor potential canonical (TRPC) channels are G protein-coupled receptor operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling. Methods and Results: Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a nonselective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1 ؊/؊ mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1 ؊/؊ mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1 ؊/؊ mice. Conclusions: From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.
On the Role of Endothelial TRPC3 Channels in Endothelial Dysfunction and Cardiovascular Disease
Cardiovascular & Hematological Agents in Medicinal Chemistry, 2012
In endothelium, calcium (Ca 2+) influx through plasma membrane Ca 2+-permeable channels plays a fundamental role in several physiological functions and in the pathogenesis of cardiovascular disease. Current knowledge on the influence of Ca 2+ influx in signaling events associated to endothelial dysfunction has grown significantly over recent years, particularly after identification of members of the Transient Receptor Potential Canonical (TRPC) family of channel forming proteins as prominent mediators of Ca 2+ entry in endothelial cells. Among TRPC members TRPC3 has been at the center of many of these physiopathological processes. Progress in elucidating the mechanism/s underlying regulation of endothelial TRPC3 and characterization of signaling events downstream TRPC3 activation are of most importance to fully appreciate the role of this peculiar cation channel in cardiovascular disease and its potential use as a therapeutic target. In this updated review we focus on TRPC3 channels, revising and discussing current knowledge on channel expression and regulation in endothelium and the roles of TRPC3 in cardiovascular disease in relation to endothelial dysfunction.
Transient Receptor Potential Channels in Cardiovascular Function and Disease
Circulation Research, 2006
Sustained elevation in the intracellular Ca 2+ concentration via Ca 2+ influx, which is activated by a variety of mechanisms, plays a central regulatory role for cardiovascular functions. Recent molecular biological research has disclosed an unexpectedly diverse array of Ca 2+ -entry channel molecules involved in this Ca 2+ influx. These include more than ten transient receptor potential (TRP) superfamily members such as TRPC1, TRPC3–6, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, and polycystin (TRPP2). Most of them appear to be multimodally activated or modulated and show relevant features to both acute hemodynamic control and long-term remodeling of the cardiovascular system, and many of them have been found to respond not only to receptor stimulation but also to various forms of stimuli. There is good evidence to implicate TRPC1 in neointimal hyperplasia after vascular injury via store-depletion–operated Ca 2+ entry. TRPC6 likely contributes to receptor-operated and mechanosensitive Ca 2+...
Circulation research, 2014
The cellular and molecular basis for post-myocardial infarction (MI) structural and functional remodeling is not well understood. Our aim was to determine if Ca2+ influx through transient receptor potential canonical (TRPC) channels contributes to post-MI structural and functional remodeling. TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca2+ entry. Cardiac myocyte-specific expression of a dominant-negative (loss-of-function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival in mice. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 overexpression in adult feline myocytes induced calcineurin (Cn)-nuclear factor of activated T-cells (NFAT)-mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPC...
Angiotensin-II-Evoked Ca2+ Entry in Murine Cardiac Fibroblasts Does Not Depend on TRPC Channels
Cells
TRPC proteins form cation conducting channels regulated by different stimuli and are regulators of the cellular calcium homeostasis. TRPC are expressed in cardiac cells including cardiac fibroblasts (CFs) and have been implicated in the development of pathological cardiac remodeling including fibrosis. Using Ca2+ imaging and several compound TRPC knockout mouse lines we analyzed the involvement of TRPC proteins for the angiotensin II (AngII)-induced changes in Ca2+ homeostasis in CFs isolated from adult mice. Using qPCR we detected transcripts of all Trpc genes in CFs; Trpc1, Trpc3 and Trpc4 being the most abundant ones. We show that the AngII-induced Ca2+ entry but also Ca2+ release from intracellular stores are critically dependent on the density of CFs in culture and are inversely correlated with the expression of the myofibroblast marker α-smooth muscle actin. Our Ca2+ measurements depict that the AngII- and thrombin-induced Ca2+ transients, and the AngII-induced Ca2+ entry and ...
Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart
Current Cardiology Reviews, 2019
Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of ...
Molecular expression and calcium signalling roles of native TRP channels in vascular cells
In the vasculature, multiple members of the TRP-superfamily of non-selective cation channels (NSCCs) are expressed. These channels mediate diverse non-voltage-gated Ca 2+-entry pathways and functions, which involve both vascular myocytes and communicating endothelial cells. Here, we provide an overview of recent progress in this area of research and discuss several specific examples of the important roles of vascular TRP channels in Ca 2+ signalling and electrophysiological responses. We especially focus on the recently discovered signal transduction mechanisms involving formation of specific complexes between TRP proteins and other better studied proteins that regulate cell calcium homeostasis, such as voltage-gated Ca 2+ channels and ryanodine receptors. Finally, we provide an overview of the progress in our understanding of TRPM8, which is known as the principal neuronal cold receptor, expression, localisation and function in the vasculature. We conclude that this channel is likely involved in complex thermal behaviour of blood vessels, better understanding of which is relevant to hypothermic and cardiovascular surgery conditions, therefore further research in this area is needed.
European heart journal, 2015
Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown. In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca(2+) concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumora...