TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice

Abstract

Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure. We here demonstrated that deletion of TRPC6 had no impact on pressure overload-induced heart failure despite inhibiting interstitial fibrosis in mice. TRPC6-deficient mouse hearts 1 week after transverse aortic constriction showed comparable increases in fibrotic gene expressions and ROS production but promoted inductions of inflammatory cytokines, compared to wild type hearts. Treatment of TRPC6-deficient mice with streptozotocin caused severe reduction of cardiac contractility with enhancing urinary and cardiac lipid peroxide levels, compared to wild type and TRPC3-deficient mice. Knockdown of TRPC6, but not TRPC3, enhanced basal expression levels of cytokines in rat cardiomyocytes. TRPC6 could interact with Nox2, but the abundance of TRPC6 was inversely correlated with that of Nox2. These results strongly suggest that Nox2 destabilization through disrupting TRPC3-Nox2 complex underlies attenuation of hyperglycemia-induced heart failure by TRPC6.

TRPC Channels in Cardiac Plasticity

“…A study of a dominant-negative mutant reported the formation of heterotetrameric TRPC channels during cardiac hypertrophy [36]. We also reported that TRPC6 functions as a negative regulator of TRPC3 coupling to NADPH oxidase 2 (Nox2) through a competitive interaction [37].…”

“…In addition, AngII-induced cardiac hypertrophy is mediated by both TRPC3 and TRPC6 [95]. However, Nox2 only functionally couples to TRPC3 [37]. As TRPC6 is able to interact with Nox2 even in the presence of TRPC3, it can function as a negative regulator of TRPC3-Nox2 coupling [37].…”

“…However, Nox2 only functionally couples to TRPC3 [37]. As TRPC6 is able to interact with Nox2 even in the presence of TRPC3, it can function as a negative regulator of TRPC3-Nox2 coupling [37]. TRPC3 expression is increased in aged and hypertensive rat atrial fibroblasts.…”

“…In a pressure-overload model, TRPC6 deletion almost completely suppressed cardiac fibrosis. This result arose from the suppression of cardiac fibroblast transdifferentiation into myofibroblasts, as there was no effect on ROS production in the heart (in contrast with TRPC3 knockout) [37]. Furthermore, the orally bioavailable TRPC6-specific inhibitor BI 749,327 could inhibit profibrotic gene expression, reduce cardiac fibrosis, and improve heart function [126].…”

TRPC channels: Dysregulation and Ca²⁺ Mishandling In Ischemic Heart Disease

“…More recently, TRPC6 was suggested to form heteromeric complex with TRPC3 and NADPH oxidase 2 (NOX2) protein in diabetic mouse heart. Nonetheless, this study used HEK293 cells to confirm the interaction between TRPC3 and TRPC6 by immunoprecipitation [33].…”