Abstract 16855: NOX4 NADPH Oxidase Mediates Diastolic Dysfunction in Stress Cardiomyopathy via Regulation of Inflammation and Fibrosis

Abstract

Acute sympathetic stress in adults results in catecholamine overload and often leads to development of stress cardiomyopathy complicated by long-lasting diastolic dysfunction. We previously reported that activation of β-adrenergic signaling in the heart increases reactive oxygen species-mediated inflammasome activation and IL-18 release, inducing myocardial inflammation, fibrosis, and dysfunction. Here we tested the hypothesis that NOX4 NADPH oxidase is a primary mediator of myocardial inflammation and diastolic dysfunction in the setting of acute stress. Acute stress in wild-type and mice with cardiomyocyte (CM)-specific Nox4 deletion ( Nox4 CM-/- ) was induced with a single dose of β-adrenergic receptor agonist isoproterenol (ISO; 5 mg/kg) injection. After 3 days, ISO-treated wild-type mice had higher myocardial H 2 O 2 , inflammasome activation and IL-1β, IL-18, IL-6, CCL2, and TNF-α levels and enhanced myocardial interstitial macrophage infiltration compared with vehicle-treated or Nox4 CM-/- mice (p<0.001). Wild-type mice left ventricles had increased presence of activated fibroblasts (periostin + ) and myofibroblasts (α-actin-2 + ) and significantly higher interstitial collagen deposition compared with Nox4 CM-/- mice 7 days post-ISO. Assessment of left ventricular function showed significantly increased mitral valve E, decreased deceleration time, decreased tissue Doppler E’ and increased E/E’ without changes in ejection fraction and end systolic or diastolic volumes, suggesting restrictive pattern of diastolic dysfunction with increased filling pressure in wild-type compared with control or Nox4 CM-/- mice. ISO treatment of ventricular CMs isolated from wild-type mice significantly increased levels of H 2 O 2 and expression of NLRP3 and cleaved caspase-1 and IL-18 as compared with Nox4 -deficient or wild-type CMs pretreated with NOX4/NOX1 inhibitor GKT137831. These data suggest that NOX4 NADPH oxidase is a critical mediator of CM sympathetic overstimulation inducing inflammasome activation and cytokine release, myocardial inflammation, and fibrosis, resulting in impaired diastolic function. Inhibiting myocardial NOX4 during acute sympathetic stress may be beneficial to preserve cardiac function.