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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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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. |
format | Online Article Text |
id | pubmed-10598408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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