Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy.

Abstract

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.

• Authors: Aleksandr E Vendrov, Han Xiao, Andrey Lozhkin, Takayuki Hayami, Guomin Hu, Matthew J Brody, Junichi Sadoshima, You-Yi Zhang, Marschall S Runge, Nageswara R Madamanchi
• Journal: Redox biology (Redox Biol) Vol. 67 Pg. 102937 (11 2023) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 37871532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Hydrogen Peroxide
• NADPH Oxidase 4
• NADPH Oxidases
• Reactive Oxygen Species
• Nox4 protein, mouse

Topics

• Animals
• Mice
• Fibrosis
• Hydrogen Peroxide (metabolism)
• Inflammation (metabolism)
• Myocytes, Cardiac (metabolism)
• NADPH Oxidase 4 (genetics, metabolism)
• NADPH Oxidases (metabolism)
• Reactive Oxygen Species (metabolism)
• Takotsubo Cardiomyopathy (metabolism, pathology)