Myocardial stretch‐induced ROS production is enhanced prior to the development of heart failure under TAC‐induced pressure overload

Abstract

Acute myocardial stretch induces reactive oxygen species (ROS) production via NADPH oxidase 2 (NOX2), referred to as stretch‐induced ROS. Recently, we demonstrated that stretch‐induced ROS serves as a physiological signal in the heart, facilitating calcium release from ryanodine receptors to maintain contractility against acute mechanical load. Chronic mechanical overload triggers oxidative stress, leading to cardiac remodelling and heart failure. Although both conditions are mechanically induced, the relationship between physiology and pathophysiological ROS production remains unclear. To address this issue, we investigated changes in stretch‐induced ROS production during the development of transverse aortic constriction (TAC)‐induced heart failure in wild‐type (WT‐TAC) and NOX2 knockout (NOX2 KO‐TAC) mice. At 2 weeks post‐TAC, no significant differences were observed in basal ROS levels or cardiac function between the two groups, and cardiac remodelling was evident in neither group. However, stretch‐induced ROS production was significantly increased in the WT‐TAC group. At 5 weeks post‐TAC, the WT‐TAC group progressed to heart failure, reduced ejection fraction with remodelling accompanied by increased basal ROS levels, while no progression was observed in the NOX2 KO‐TAC group. The present study demonstrated that in TAC‐induced heart failure, physiological acute stretch‐induced ROS production increases prior to the elevation of oxidative stress. This suggests that the enhancement of physiological stretch‐induced ROS levels in response to chronic pressure overload may induce excessive ROS production, contributing to heart failure. Therefore, pathological oxidative stress may originate from the physiological stretch‐induced ROS production pathway. image