TRPC1 Channels Are Critical for Hypertrophic Signaling in the Heart

Abstract

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. (Circ Res. 2009;105:1023-1030.)Key Words: transient receptor potential channels Ⅲ G protein receptor signaling Ⅲ cardiac hypertrophy C ardiac myocytes respond to changing mechanical workloads by altering the frequency and amplitude of their calcium transients. 1,2 Encoded in these calcium transients are signals that alter not only the immediate contractile response but also initiate and maintain a remodeling response that adjusts cellular mass, ionic currents, kinetic properties of contractile proteins, and metabolic capacity. 3 It is likely that persistence of these signals modulate the calcium signaling events resulting in a hypertrophic response and adverse remodeling. To identify the proximal signals that regulate cardiac hypertrophy, attention has begun to focus on ion channels because they may link mechanical activity to cell signaling. 4 Recent work has raised the possibility that hypertrophic agonists linked to G-protein coupled receptors activate calcium entry through transient receptor potential canonical (TRPC) channels. [5][6][7][8][9][10] TRPC channels encompass a large family of nonselective cation channels found in many different cell types. 11 TRPC channels are activated downstream of G-protein receptor through the phospholipase C signaling by inositol trisphosphate (TRPC1/4/5) or by diacyl glycerol (TRPC3/6/7). 5,12 More recently TRPC1/6 channels were found to be mechanosensitive channels that mediate nonselective cation entry in response to i...

TRPC channels are necessary mediators of pathologic cardiac hypertrophy

“…Moreover, Trpc1 −/− mice were shown to develop less cardiac hypertrophy in response to 8 weeks of pressure-overload stimulation or 4 weeks of AngII infusion (10). Although our study is in agreement, we identified several concepts that further establish an overarching Ca 2+ regulatory paradigm in the heart.…”

“…More recently, some data have emerged suggesting that TRPC channels are required for cardiac hypertrophy, because Trpc1 −/− mice and use of the TRPC3 inhibitory compound Pyr3 showed reduced pressure-overload growth (10,11). However, it remains unknown whether endogenous TRPC channels and associated Ca 2+ influx are altered in pathologic cardiac hypertrophy and which subfamily might be required for pathologic growth.…”

PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes

“…Based on our observation that a single point mutation within the TRPC3 pore causes specific elimination of Ca 2+ permeation, we set out to use this genetically engineered cation channel to explore the cellular impact of the TRPC3-mediated monovalent conductance and to identify downstream signaling pathways that are specifically linked to either the monovalent transport or to Ca 2+ entry through the channel pore. Because the TRPC monovalent conductance is considered of particular importance in excitable cells, and because recent studies have demonstrated the relevance of TRPC channels in cardiac pathophysiology (2,4,7,18) we focused on the cardiac system, using the HL-1 murine atrial cell line. Initially, we compared basic properties of TRPC3 signaling in HL-1 cells with those in the well characterized electrically nonexcitable HEK293 system.…”

Signaling effectors underlying pathologic growth and remodeling of the heart

“…Cardiac-specific expression of dn-TRPC3, dn-TRPC4, or dn-TRPC6 each antagonized the degree of cardiac hypertrophy after pressure overload stimulation or infusion of phenylephrine/angiotensin II (148). Similarly, mice deficient in Trpc1 showed reduced cardiac hypertrophy and disease after pressure overload or neuroendocrine agonist stimulation (149). These results suggest that an appropriately designed inhibitor that blocks one or more of these TRPC channels might be an effective therapeutic for cardiac hypertrophy or the transition to heart failure.…”