TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling

Abstract

The heart responds to injury and chronic pressure overload by pathologic growth and remodeling, which frequently result in heart failure and sudden death. Calcium-dependent signaling pathways promote cardiac growth and associated changes in gene expression in response to stress. The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate cation entry into cells in response to a variety of signals, and in skeletal muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is increased in response to neurostimulation and calcineurin signaling. Here we show that TRPC6 was upregulated in mouse hearts in response to activated calcineurin and pressure overload, as well as in failing human hearts. Two conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of β-myosin heavy chain, a sensitive marker for pathologic hypertrophy. These findings implicate TRPC6 as a positive regulator of calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory loop that drives pathologic cardiac remodeling.

TRPC channels are necessary mediators of pathologic cardiac hypertrophy

“…Simple overexpression of TRPC3 or TRPC6 in the mouse heart was sufficient to induce Ca 2+ entry and enhance the cardiac hypertrophic response (4,5). Mechanistically, we and others have shown that TRPC channels engage calcineurin-NFAT signaling in the heart, a well-known prohypertrophic pathway that is both necessary and sufficient for growth (4)(5)(6)(7). Indeed, deletion of calcineurin Aβ reduced hypertrophic inducibility by TRPC3 overexpression in the heart (5).…”

“…More provocatively, TRPC channels probably coexist with TRPM and TRPP subclasses of channels in even larger channel complexes (16,17). Because all TRPC family members have been detected in the heart, some of which are up-regulated by hypertrophy (4)(5)(6)(7)23), it is likely that many combinations of tetramers are possible and can generate unique cation influx properties. However, combined inhibition of both subfamilies in dnTRPC4, dnTRPC3 DTG mice completely eliminated all TAC-associated Ca 2+ entry, suggesting that not all TRPC complexes show crossoligomerization in the heart.…”

“…Augmentation in intracellular Ca 2+ is thought to be critically involved in signaling cardiac hypertrophy, in part through the Ca 2+ -activated protein phosphatase calcineurin, which leads to activation of the transcription factor, nuclear factor of activated T cells (NFAT), which induces hypertrophic response genes (3). Transient receptor potential canonical (TRPC) channels are cation-selective influx channels that can initiate cardiac hypertrophy when overexpressed, in part because of increased Ca 2+ influx and calcineurin activation (4)(5)(6)(7). Functional TRPC channels are comprised of homo-or heterotetramers between either TRPC1/4/5 or TRPC3/ 6/7 subfamily members, although overexpression of any one subunit alone can produce enhanced currents (8).…”

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

“…However, several recent studies have provided evidence that TRPCs may also be functional in the heart (18,28,30). Ohba et al (30) demonstrated that hypertrophic stimuli increased TRPC1 expression both in the intact heart and in isolated cardiomyocytes (30).…”

254C>G: a TRPC6 promoter variation associated with enhanced transcription and steroid-resistant nephrotic syndrome in Chinese children

“…-254C>G localizes within the promoter region of the TRPC6 gene, which contains several transcription binding sites, such as nuclear factor of activated T cells (19,20). In cardiomyocytes, TRPC6 was upregulated through the calcineurin-nuclear factor of activated T cells signaling pathway leading to cardiac Articles Kuang et al…”