Cardiomyocyte NOX4 knockout or pharmacological inhibition reduced myocardial inflammation, macrophage infiltration, fibrosis, and preserved diastolic function in mice with stress cardiomyopathy.
Does NOX4 inhibition or knockout prevent inflammation and diastolic dysfunction in a mouse model of stress cardiomyopathy?
Cardiomyocyte NOX4-dependent ROS mediates resident macrophage activation, inflammation, fibrosis, and diastolic dysfunction in stress cardiomyopathy, suggesting NOX4 as a potential therapeutic target.
In acute sympathetic stress, catecholamine overload can lead to stress cardiomyopathy. We tested the hypothesis that cardiomyocyte NOX4 (NADPH oxidase 4)-dependent mitochondrial oxidative stress mediates inflammation and diastolic dysfunction in stress cardiomyopathy. Isoproterenol (ISO; 5 mg/kg) injection induced sympathetic stress in wild-type and cardiomyocyte (CM)-specific Nox4 knockout (Nox4CM−/−) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H2O2 levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4CM−/− mice. Spectral flow cytometry and t-SNE analysis of cardiac cell suspensions showed significant increases in pro-inflammatory and pro-fibrotic embryonic-derived resident (CCR2−MHCIIhiCX3CR1hi) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4CM−/− mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2−MHCIIloCX3CR1lo) macrophages. A significant increase in cardiac fibroblast activation and interstitial collagen deposition and a restrictive pattern of diastolic dysfunction with increased filling pressure was observed in wild-type hearts compared with Nox4CM−/− 7 days post-ISO. A selective NOX4 inhibitor, GKT137831, reduced myocardial mitochondrial ROS, macrophage infiltration, and fibrosis in ISO-injected wild-type mice, and preserved diastolic function. Our data suggest sympathetic overstimulation induces resident macrophage (CCR2−MHCII+) activation and myocardial inflammation, resulting in fibrosis and impaired diastolic function mediated by CM NOX4-dependent ROS.
Vendrov et al. (Thu,) conducted a other in Stress cardiomyopathy. Cardiomyocyte NOX4 knockout or NOX4 inhibitor (GKT137831) vs. Wild-type mice was evaluated on Myocardial inflammation, fibrosis, and diastolic dysfunction. Cardiomyocyte NOX4 knockout or pharmacological inhibition reduced myocardial inflammation, macrophage infiltration, fibrosis, and preserved diastolic function in mice with stress cardiomyopathy.