Physiological role of TRPC6 upregulation in hyperglycemic rodent hearts

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.