Abstract
Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities.
Highlights
Nox[2] is a microtubule-associated ROS-producing enzyme that acts as a key mediator of mechanotransductive signaling in normal hearts[4]
Pressure overload induced by transverse aortic constriction (TAC) causes heart failure characterized by left ventricular (LV) hypertrophy and associated myocardial stiffness
These results indicate that both TRPC3 and p22phox proteins are co-localized in T-tubule in cardiomyocytes
Summary
Nox[2] is a microtubule-associated ROS-producing enzyme that acts as a key mediator of mechanotransductive signaling in normal hearts[4]. Transient ROS production induced by mechanical stretch during diastolic filling triggers a burst of Ca2+ sparks through oxidative modification-dependent activation of ryanodine receptors. Persistent Nox2-derived ROS production in response to pressure overload in mice leads to oxidative stress through Nox2-derived ROS-induced ROS release from mitochondria and participates in the transition from cardiac adaptation to maladaptation[5,6]. Recent studies using TRPC3-deficient C57BL/6 J mice have shown that selective inhibition of TRPC3 does not mitigate the LV hypertrophy induced by pressure overload, though deletion of multiple TRPC channels, including TRPC3/C6 and TRPC1/C4, suppresses LV hypertrophy in mice[8,11]. TRPC3 acts as a PRROS that stabilizes Nox[2] activity through physical interaction, leading to amplification of ROS-dependent maladaptive signaling induced by mechanical stretch during diastolic filling in cardiomyocytes
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