scholarly journals Involvement of transient receptor potential proteins in cardiac hypertrophy

2007 ◽  
Vol 1772 (8) ◽  
pp. 885-894 ◽  
Author(s):  
Romain Guinamard ◽  
Patrick Bois
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor

Abstract 164: Microdomain Specific Effects of Transient Receptor Potential Channels on Pathological Cardiac Hypertrophy and Myocyte Contractility

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Catherine A Makarewich ◽  
Hongyu Zhang ◽  
Hui Gao ◽  
Robert N Correll ◽  
Jason M Duran ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Trpc Channels ◽  
Ec Coupling ◽  
Transient Receptor ◽  
Myocyte Contractility ◽  
Signaling Domains ◽  
Ca2 Channels

Hypothesis: Ca2+ influx through transient receptor potential canonical (TRPC) channels and L-type Ca2+ channels (LTCCs) within caveolin-3 (Cav3) stabilized signaling microdomains provide a unique source of Ca2+ to activate pathologic cardiac hypertrophy through calcineurin (Cn)-mediated nuclear factor of activated T-cells (NFAT) signaling. We suggest that a distinct and separate population of TRPC channels localized in excitation-contraction (EC) coupling microdomains may have potent effects on myocyte contractility independent of Cav3 signaling domains. Methods and Results: Membrane localization studies and immunohistochemistry show that TRPC channels and LTCCs co-localize to Cav3 signaling microdomains. To explore a role for these caveolae based Ca2+ channels in the initiation of Cn-NFAT signaling we used an adenoviral NFAT-GFP reporter in cultured adult feline myocytes (AFMs). Infecting AFMs with ad-TRPC3 dramatically increased NFAT translocation, which was inhibited with dominant negative ad-dnTRPC6. Expression of a Cav3 targeted LTCC blocker (ad-Cav-Rem) reduced NFAT translocation while a targeted LTCC activator (ad-Cav-β2a) significantly increased NFAT activation. Neither LTCC modulator had significant effects on Ca2+ current or contractility in AFMs but we found that the expression of TRPC3 reduced myocyte contractility and induced spontaneous Ca2+ spark activity that was exacerbated by the DAG activator OAG. Moreover, dnTRPC6 blocked spontaneous Ca2+ sparks even in the presence of OAG. Immunohistochemistry analysis revealed the presence of TRPC channels in transverse tubules, consistent with the idea that they could have direct effects on EC coupling microdomains. Conclusions: Our data show that TRPC channels and LTCCs co-localize to Cav3 signaling domains where they generate a unique Ca2+ microenvironment that directly regulates Cn-NFAT signaling. Our findings also suggest that a separate and distinct population of TRPC channels within EC coupling microdomains cause reduced myocyte contractility by inducing SR Ca2+ leak and Ca2+ spark activity.

Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation

2017 ◽  
Vol 35 (3) ◽  
pp. 602-611 ◽  
Author(s):  
Sheryl E. Koch ◽  
Adrien Mann ◽  
Shannon Jones ◽  
Nathan Robbins ◽  
Abdullah Alkhattabi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

scholarly journals Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

2012 ◽  
Vol 4 (2) ◽  
pp. 97-107 ◽  
Author(s):  
Yingmei Zhang ◽  
Linlin Li ◽  
Yinan Hua ◽  
Jennifer M. Nunn ◽  
Feng Dong ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cold Stress ◽  
Cold Exposure ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Maximal Velocity ◽  
Eta Receptor ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Abstract Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.

scholarly journals TRPV1 Activation Attenuates High-Salt Diet-Induced Cardiac Hypertrophy and Fibrosis through PPAR-δUpregulation

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Feng Gao ◽  
Yi Liang ◽  
Xiang Wang ◽  
Zongshi Lu ◽  
Li Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Protective Role ◽  
High Salt ◽  
Transient Receptor Potential Vanilloid ◽  
High Salt Diet ◽  
Salt Diet ◽  
Transient Receptor

High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptorsδ(PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardiac hypertrophy and fibrosis and the effect of cross-talk between TRPV1 and PPAR-δon suppressing high-salt diet-generated oxidative stress. In this study, high-salt diet-induced cardiac hypertrophy and fibrosis are characterized by significant enhancement of HW/BW%, LVEDD, and LVESD, decreased FS and EF, and increased collagen deposition. These alterations were associated with downregulation of PPAR-δ, UCP2 expression, upregulation of iNOS production, and increased oxidative/nitrotyrosine stress. These adverse effects of long-term high-salt diet were attenuated by chronic treatment with capsaicin. However, this effect of capsaicin was absent in TRPV1−/−mice on a high-salt diet. Our finding suggests that chronic dietary capsaicin consumption attenuates long-term high-salt diet-induced cardiac hypertrophy and fibrosis. This benefit effect is likely to be caused by TRPV1 mediated upregulation of PPAR-δexpression.

Abstract 537: Sildenafil Suppresses Cardiac Hypertrophy through Inhibition of Canonical Transient Receptor Potential Cation Channel 6 Expression in Cardiac Myocytes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Norimichi Koitabashi ◽  
Manling Zhang ◽  
Eiki Takimoto ◽  
Takahiro Nagayama ◽  
David A Kass
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Canonical Transient Receptor Potential ◽  
Transient Receptor

Background: We have shown that a phosphodiesterase 5A (PDE5A) inhibitor, sildenafil blocks cardiac pathological hypertrophy through inhibition of Gαq mediated signaling and calcineurin (Cn) signaling. However, the precise molecular mechanism is still unknown. Recently canonical transient receptor potential cation channel 6 (TRPC6) and its up-regulation have been shown to play a critical role for Gαq-mediated Cn activation in pathogenesis of cardiac hypertrophy. Therefore, we hypothesized that PDE5A inhibition blocks TRPC6 gene induction in cardiac myocytes and thus prevents cardiac hypertrophy. Methods and Results: We examined TRPC6 expression levels using real-time RT-PCR in hypertrophied mouse heart created by transverse aortic constriction (TAC). TRPC6 mRNA expression was significantly increased after TAC. Sildenafil effectively attenuated TAC-induced hypertrophy, Cn protein level and upregulation of TRPC6 mRNA. To investigate role of TRPC6 in sildenafil’s anti-hypertrophic effects, we studied cultured adult mouse cardiac myocytes (AMCM) and neonatal rat cardiac myocytes (NRCM). Stimulation with Endothelin 1 (ET1) or angiotensin II (AngII) increased cell surface area, leucine uptake, Cn protein expression and TRPC6 gene expression. Sildenafil dose-dependently blocked these increases. 8-bromo cGMP also blocked TRPC6 induction by ET1 and AngII. In addition, 8-bromo cGMP stimulation following adenovirus-mediated overexpression of cGMP-dependent protein kinase I-α (PKG) showed a marked decrease in TRPC6 expression. These results suggest that PKG activation regulates TRPC6 gene in cardiac myocytes. Using adenovirus-based expression of artificial PDE5A-gene silencing miRNA, PDE5 protein was effectively knocked down both in NRCM and AMCM. Importantly, PDE5-miRNA completely blocked ET1-mediated increase of Cn and TRPC6 same as sildenafil. Conclusion: Sildenafil effectively blocks TRPC6 induction both in vivo and in vitro . TRPC6 gene regulation is PKG and PDE5A dependent in cardiac myocytes. Given that TRPC6 induction triggers Gαq-mediated maladaptive signaling, especially Cn, these data show that the inhibition of TRPC6 gene expression contributes to the Gαq-coupled anti-hypertrophic mechanism of sildenafil.

Abstract 138: Transient Receptor Potential Channel C1 Deficiency Protects the Murine Heart from Pressure Overload

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Malini Seth ◽  
Zhu-Shan Zhang ◽  
Lan Mao ◽  
Jarrett Burch ◽  
Victoria Graham ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Trpc Channels ◽  
Loss Of Function ◽  
Aortic Banding ◽  
Trpc1 Channels ◽  
Transient Receptor

Transient receptor potential canonical (TRPC) channels are non-selective cation channels that are activated in response to G-protein coupled receptor activation, depletion of internal stores and mechanical stretch. Recent reports suggest that cardiac TRPC channels mediate calcineurin dependent cardiac hypertrophy, yet few details exist as to the mechanism for activation of these channels. Here, we provide evidence that TRPC1 channels are the dominant TRPC channel in mouse cardiomyocytes and cardiac TRPC1 protein expression is augmented by seven fold following thoracic aortic banding (TAC). In addition, we provide the first loss of function studies to show that mice lacking TRPC1 channels developed significantly less cardiac hypertrophy following pressure overload induced by thoracic aortic banding suggesting that TRPC1 may confer deleterious calcium entry. Whole cell voltage clamp studies of isolated adult cardiomyocytes reveal a non-selective cation current that is induced by pressure overload that is absent in TRPC1−/− cardiomyocytes and in which TRP blockers such as gadolinium, 2-amino biphenyl boric acid and SKF96365 inhibit the TAC induced current. Finally, neonatal cardiomyocytes lacking functional TRPC1 display reduced TRPC current in response to cell stretch or angiotensin-II; the functional consequence of which includes reduced calcium oscillation frequency and reduced BNP expression. These results provide the first loss of function evidence for TRPC1 channels in cardiac hypertrophy and implicate TRPC1 as a stretch activated channel.

Inositol lipids and TRPC channel activation

2007 ◽  
Vol 74 ◽  
pp. 37-45 ◽  
Author(s):  
James W. Putney
Keyword(s):  
Plasma Membrane ◽  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Calcium Signalling ◽  
Receptor Potential ◽  
Breakdown Product ◽  
Channel Activation ◽  
Inositol Lipids ◽  
Transient Receptor ◽  
Secondary Mechanism

The original hypothesis put forth by Bob Michell in his seminal 1975 review held that inositol lipid breakdown was involved in the activation of plasma membrane calcium channels or ‘gates’. Subsequently, it was demonstrated that while the interposition of inositol lipid breakdown upstream of calcium signalling was correct, it was predominantly the release of Ca2+ that was activated, through the formation of Ins(1,4,5)P3. Ca2+ entry across the plasma membrane involved a secondary mechanism signalled in an unknown manner by depletion of intracellular Ca2+ stores. In recent years, however, additional non-store-operated mechanisms for Ca2+ entry have emerged. In many instances, these pathways involve homologues of the Drosophila trp (transient receptor potential) gene. In mammalian systems there are seven members of the TRP superfamily, designated TRPC1–TRPC7, which appear to be reasonably close structural and functional homologues of Drosophila TRP. Although these channels can sometimes function as store-operated channels, in the majority of instances they function as channels more directly linked to phospholipase C activity. Three members of this family, TRPC3, 6 and 7, are activated by the phosphoinositide breakdown product, diacylglycerol. Two others, TRPC4 and 5, are also activated as a consequence of phospholipase C activity, although the precise substrate or product molecules involved are still unclear. Thus the TRPCs represent a family of ion channels that are directly activated by inositol lipid breakdown, confirming Bob Michell's original prediction 30 years ago.

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