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

• DOI: 10.1007/s00395-011-0204-x
• Publication Date: 2011-07-18T20:44:18Z
• Authors: Yulong Hu; Hanwen Zhang; Yan Lu; Hui Bai; Yiming Xu; Xudong Zhu; Rongmei Zhou; Jingjing Ben; Yong Xu; Qi Chen
• Keywords: Macrophage polarization; M2 Macrophage; Scavenger Receptor

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.