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

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) in...

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Autores principales: Vendrov, Aleksandr E., Xiao, Han, Lozhkin, Andrey, Hayami, Takayuki, Hu, Guomin, Brody, Matthew J., Sadoshima, Junichi, Zhang, You-Yi, Runge, Marschall S., Madamanchi, Nageswara R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598408/
https://www.ncbi.nlm.nih.gov/pubmed/37871532
http://dx.doi.org/10.1016/j.redox.2023.102937
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author Vendrov, Aleksandr E.
Xiao, Han
Lozhkin, Andrey
Hayami, Takayuki
Hu, Guomin
Brody, Matthew J.
Sadoshima, Junichi
Zhang, You-Yi
Runge, Marschall S.
Madamanchi, Nageswara R.
author_facet Vendrov, Aleksandr E.
Xiao, Han
Lozhkin, Andrey
Hayami, Takayuki
Hu, Guomin
Brody, Matthew J.
Sadoshima, Junichi
Zhang, You-Yi
Runge, Marschall S.
Madamanchi, Nageswara R.
author_sort Vendrov, Aleksandr E.
collection PubMed
description 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 (Nox4(CM−/−)) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H(2)O(2) levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4(CM−/−) 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(−)MHCII(hi)CX3CR1(hi)) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4(CM−/−) mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2(−)MHCII(lo)CX3CR1(lo)) 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 Nox4(CM−/−) 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.
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spelling pubmed-105984082023-10-26 Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy Vendrov, Aleksandr E. Xiao, Han Lozhkin, Andrey Hayami, Takayuki Hu, Guomin Brody, Matthew J. Sadoshima, Junichi Zhang, You-Yi Runge, Marschall S. Madamanchi, Nageswara R. Redox Biol Research Paper 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 (Nox4(CM−/−)) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H(2)O(2) levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4(CM−/−) 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(−)MHCII(hi)CX3CR1(hi)) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4(CM−/−) mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2(−)MHCII(lo)CX3CR1(lo)) 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 Nox4(CM−/−) 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. Elsevier 2023-10-19 /pmc/articles/PMC10598408/ /pubmed/37871532 http://dx.doi.org/10.1016/j.redox.2023.102937 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Vendrov, Aleksandr E.
Xiao, Han
Lozhkin, Andrey
Hayami, Takayuki
Hu, Guomin
Brody, Matthew J.
Sadoshima, Junichi
Zhang, You-Yi
Runge, Marschall S.
Madamanchi, Nageswara R.
Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title_full Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title_fullStr Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title_full_unstemmed Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title_short Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
title_sort cardiomyocyte nox4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598408/
https://www.ncbi.nlm.nih.gov/pubmed/37871532
http://dx.doi.org/10.1016/j.redox.2023.102937
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