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Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization

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Abstract

Classically (M1) and alternatively (M2) activated macrophage subsets play differential roles in left ventricular remodeling after myocardial infarction (MI). The precise mechanism underlying the regulation of M1/M2 polarization during MI is unknown. We hypothesized that class A scavenger receptor (SR-A), a key modulator of inflammation, may steer macrophage polarization, which in turn influences cardiomyocytes necrosis after MI. MI was induced in wild type (WT) and SR-A deficient (SR-A−/−) mice by left anterior descending coronary artery ligation. Cardiac function deterioration, ventricular dilatation and fibrosis were all exacerbated in SR-A−/− mice following MI compared to WT littermates. Meanwhile, enhanced M1 macrophage polarization was observed in SR-A−/− mice, along with increased production of M1 signature cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) as demonstrated by immunohistochemistry, flow cytometry, quantitative real-time PCR, and ELISA assays. Moreover, activation of the activated apoptosis signal regulating kinase 1 (ASK1)/p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathway was markedly elevated in SR-A−/− animals post-MI. Most importantly, transplantation using bone marrow from SR-A+/+ mice partially restored M1 macrophages and significantly augmented left ventricular fractional shortening in SR-A−/− mice. SR-A attenuated MI-induced cardiac remodeling by suppressing macrophage polarization toward a skewed M1 phenotype, reducing secretion of IL-1β, IL-6, and TNF-α, and dampening the ASK1/p38/NF-κB signaling pathway. Therefore, SR-A may exert a protective effect against MI, which may represent a new interventional target for treatment of post-infarct remodeling and subsequent heart failure.

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Acknowledgments

This work was supported by National Natural Science Foundation of China Grants (NO. 30730044 and 81070120 to Qi Chen), National Basic Research Program (973) (No. 2011CB503903 to Yong Ji), and National Natural Science Foundation of China (NO.81000118 to Jingjing Ben).

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Authors and Affiliations

  1. Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, 210029, China

    Yulong Hu, Hanwen Zhang, Yan Lu, Hui Bai, Yiming Xu, Xudong Zhu, Rongmei Zhou, Jingjing Ben, Yong Xu & Qi Chen

  2. State key laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, China

    Yulong Hu, Xudong Zhu, Jingjing Ben & Qi Chen

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  1. Yulong Hu
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  2. Hanwen Zhang
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  3. Yan Lu
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Correspondence to Jingjing Ben or Qi Chen.

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Hu, Y., Zhang, H., Lu, Y. et al. Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization. Basic Res Cardiol 106, 1311–1328 (2011). https://doi.org/10.1007/s00395-011-0204-x

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