Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 210029, China.
Basic Res Cardiol. 2011 Nov;106(6):1311-28. doi: 10.1007/s00395-011-0204-x. Epub 2011 Jul 19.
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.
经典（M1）和替代性（M2）激活的巨噬细胞亚群在心肌梗死后左心室重构中发挥不同作用。在心肌梗死后调节 M1/M2 极化的确切机制尚不清楚。我们假设 A 型清道夫受体（SR-A），炎症的关键调节剂，可能会引导巨噬细胞极化，进而影响心肌梗死后的心肌细胞坏死。通过左前降支冠状动脉结扎诱导野生型（WT）和 SR-A 缺陷（SR-A(-/-)）小鼠的 MI。与 WT 同窝仔相比，SR-A(-/-)小鼠的心肌梗死后心脏功能恶化、心室扩张和纤维化均加剧。同时，在 SR-A(-/-)小鼠中观察到 M1 巨噬细胞极化增强，以及 M1 特征细胞因子（包括白细胞介素 1β（IL-1β）、IL-6 和肿瘤坏死因子-α（TNF-α））的产生增加，通过免疫组织化学、流式细胞术、定量实时 PCR 和 ELISA 测定证实。此外，在 MI 后 SR-A(-/-)动物中，激活凋亡信号调节激酶 1（ASK1）/p38 丝裂原活化蛋白激酶（MAPK）/核因子-κB（NF-κB）信号通路明显升高。最重要的是，使用来自 SR-A(+/+)小鼠的骨髓移植部分恢复了 M1 巨噬细胞，并显著增加了 SR-A(-/-)小鼠的左心室短轴缩短分数。SR-A 通过抑制巨噬细胞向偏 M1 表型极化来减弱 MI 诱导的心脏重塑，减少 IL-1β、IL-6 和 TNF-α 的分泌，并抑制 ASK1/p38/NF-κB 信号通路。因此，SR-A 可能对 MI 具有保护作用，这可能代表治疗梗死后重塑和随后心力衰竭的新介入靶点。
