TRPC Channels As Effectors of Cardiac Hypertrophy

Eder, Petra; Molkentin, Jeffery D.

doi:10.1161/circresaha.110.225888

Cited by 214 publications

(185 citation statements)

References 79 publications

(114 reference statements)

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“…2B). Each of these genes has been reported to be upregulated in pathological cardiac hypertrophy in several animal models (including rat) and human heart failure, except for TRPC1, in which, instead, TRPC5 and TRPC6 are up-regulated in human (34)(35)(36)(37)(38). We also observed stretch-dependent up-regulation of genes encoding for cytoskeletal proteins (Fig.…”

Section: Resultsmentioning

confidence: 54%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

124

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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structurefunction relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α-to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart. organs on chips | mechanotransduction | muscular thin films | microarray | contraction

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Section: Resultsmentioning

confidence: 54%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

124

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“…In addition, TRPC3 and TRPC6 have also been shown to contribute to the development of ANG II-induced hypertrophy (79), and SOCE and NFAT translocation have been shown to be increased in HEK293 cells overexpressing TRPC1 (78). Interestingly, as recently as 2011, although describing the significance of SOCE in cardiomyocytes as a mystery, Eder and Molkentin nevertheless concluded that "TRPC channels are bona fide regulators of cardiac hypertrophy associated with pathological events and neuroendocrine signaling" (18).…”

Section: Orai1/trpcmentioning

confidence: 99%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

108

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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“…However, selective deletion of the AII receptor 1 (AT-R1) in the kidney ameliorated AIIinduced cardiac hypertrophy, suggesting that the cardiac AT-R1 is dispensable for the induction of this response (6), whereas transgenic mice that overexpress the human AT-R1 specifically in CMs develop hypertrophy, fibrosis, dysfunctions, and early death (7). Furthermore, activation of TRPC channels followed by elevated [Ca 2+ ] i may contribute to the induction of the cardiac hypertrophy gene response (8)(9)(10)(11). Again, TRPC3 and TRPC6 channels are negatively regulated by cGKI (12)(13)(14).…”

mentioning

confidence: 99%

“…This effect is postulated to be caused by an increased activity of RGS2 (19), and in part by the direct regulation of TRPC3/6 conductance by cGKI (11,14) mentioned above. However, two clinical studies did not report positive therapeutic results after prolonged treatment of diastolic dysfunction with sildenafil (20,21).…”

mentioning

confidence: 99%

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

Patrucco

Domes

Sbroggiò

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg·kg −1 ·d −1 ) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.PKGI | PDE | cardiac failure | hypertension | NO/cyclic GMP system

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TRPC Channels As Effectors of Cardiac Hypertrophy

Cited by 214 publications

References 79 publications

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

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