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Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction
Shanshan Cai, … , Jennifer Davis, Rong Tian
Shanshan Cai, … , Jennifer Davis, Rong Tian
Published December 8, 2022
Citation Information: J Clin Invest. 2023;133(4):e159498. https://doi.org/10.1172/JCI159498.
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Research Article Cardiology Metabolism

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

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Abstract

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3–7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

Authors

Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian

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Figure 5

Activation and proliferation of cardiac myofibroblasts is suppressed in mKO mice after MI.

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Activation and proliferation of cardiac myofibroblasts is suppressed in ...
(A) Representative immunofluorescence images of CF proliferation. LysMcre and mKO mouse hearts were prelabeled with 100 mg/kg EdU 24 hours and 9 hours before harvesting on post-MI day 3. Cryosections of the heart were assessed by Click iT kit to detect Edu (pink) and PDGFRα (green). Nuclei are stained with Hoechst (blue). Scale bars: 50 μm. Arrows show proliferating myofibroblasts, i.e., PDGFRα+ and EdU+ cells. (B) Quantification of proliferating myofibroblasts as a percentage of all PDGFRα+ cells in the infarcted region (n = 4–5/group). Dots represent biological replicates, and data represent the mean ± SEM. ***P < 0.001, by unpaired, 2-tailed Student’s t test. (C) Immunofluorescence imaged of fibronectin in infarcted heart tissue at post-MI day 7. Scale bars: 50 μm. (D) Quantitative morphometry of immunostaining, in which the relative abundance of the stained area was calculated by averaging the results from multiple independent images from f/f and mKO mice (n = 4/group). **P < 0.01, by unpaired, 2-tailed Student’s t test. (E) Representative immunofluorescence images of α-SMA staining in the infarcted region at post-MI day 7: fibronectin (red), α-SMA (green), Hoechst (blue). Scale bars: 50 μm. (F) Quantification of α-SMA+ staining in heart tissue at post-MI day 7 (n = 4 per group). *P < 0.05, by unpaired, 2-tailed Student’s t test. (G and H) mRNA expression levels of col1α (G) and α-SMA (H) were determined by qPCR in CFs treated with supernatants of spent medium of cM cells or control medium. cM cells were isolated from infarcted heart tissue at post-MI day 3 and then cultured in DMEM with 10% FBS for 2 hours or 24 hours. The supernatants of the spent medium or control medium were collected and added to the CF culture for an additional 24 hours. RNA was extracted from CFs and then subjected to qPCR (n = 4/group). Dots represent biological replicates, and data represent the mean ± SEM. **P < 0.01 and ***P < 0.001, by 1-way ANOVA.

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