Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
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
Affiliations
Aleksandr E. Vendrov
Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
Han Xiao
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, 100191, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, 100191, China
Andrey Lozhkin
Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
Takayuki Hayami
Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
Guomin Hu
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, 100191, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, 100191, China
Matthew J. Brody
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
Junichi Sadoshima
Rutgers New Jersey Medical School, Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, NJ, 07101, USA
You-Yi Zhang
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, 100191, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, 100191, China
Marschall S. Runge
Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
Nageswara R. Madamanchi
Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author. Department of Internal Medicine, University of Michigan, 7301A Medical Science Research Building III, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109-5644, USA.
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.
