Physiological role of TRPC6 upregulation in hyperglycemic rodent hearts

[Speaker] Sayaka Oda:1,2
[Co-author] Takuro Numaga-Tomita:1,2, Akiyuki Nishimura:1,2, Motohiro Nishida:1,2,3
1:Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Japan, 2:Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Japan, 3:Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan

<Background> Receptor-activated calcium-permeable cation channels (RACCs) have been attracted attention as molecular targets of next generation calcium channel blocker. Transient receptor potential canonical (TRPC) proteins are molecular entities of RACCs and reportedly upregulated in various diseases and pathologies. Especially in the cardiovascular systems, diacylglycerol-activated TRPC channel proteins (TRPC3 and TRPC6) are reportedly upregulated in pathologically hypertrophied hearts. We recently revealed that upregulation of TRPC3 proteins negatively regulates proteasome-dependent degradation of NADPH oxidase 2 (Nox2), a reactive oxygen species (ROS)-generating enzyme, independently of channel activity, resulting in induction of ROS-dependent cardiac fibrosis (stiffness) and myocardial atrophy in mouse hearts. In contrast, there is no direct causal-relationship between TRPC6 and heart failure, although TRPC6 is known to be highly upregulated in various pathologies including hyperglycemia, ischemia, and hemodynamic loading. Therefore, we investigated the role of TRPC6 upregulation in hyperglycemia-induced risk of heart failure, form perspective of the crosstalk between TRPC6 and TRPC3-Nox2 protein complex.
<Method/Results> The abundance of TRPC6 protein was increased while that of Nox2 protein was decreased in streptozotocin (STZ)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs) treated with high glucose (50 mM). Treatment of wild type, TRPC3-deleted and TRPC6-deleted mice with STZ showed significant increases in blood glucose level to a similar extent, but only TRPC6-deficient mice showed severe reduction of cardiac contractility and excess production of oxidative stress. TRPC6-silenced NRCMs treated with high glucose showed marked increases in ROS production and expressions of inflammatory cytokines. Both TRPC3 and TRPC6 interacted with Nox2, but only TRPC3 increased Nox2 protein abundance. TRPC6 could interact with Nox2 as well as TRPC3, but TRPC6 never increased Nox2 protein abundance in HEK293 cells. TRPC6 channel activity was not required for counteracting TRPC3-Nox2 complex by TRPC6 protein.
<Conclusion> Upregulation of TRPC6 in cardiomyocyte exposed to hyperglycemic condition inhibits formation of TRPC3-Nox2 complex and suppresses increase of Nox2 expression. These results suggest that TRPC6 upregulation contributes to adaptation of the heart against hyperglycemic stress.

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