Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization
Class A scavenger receptor attenuates myocardial infarction-induced cardiomyocyte necrosis through suppressing M1 macrophage subset polarization
复制标题
A 类清道夫受体通过抑制 M1 巨噬细胞亚群极化来减轻心肌梗死引起的心肌细胞坏死
DOI：
10.1007/s00395-011-0204-x
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发表时间：
2011-11-01
影响因子：
9.5
通讯作者：
Chen, Qi
中科院分区：
文献类型：
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作者：
Hu, Yulong;Zhang, Hanwen;Chen, Qi
经典（M1）和替代（M2）激活的巨噬细胞亚群在心肌梗塞（MI）后的左心室重塑中发挥不同的作用。 MI 期间 M1/M2 极化调节的精确机制尚不清楚。我们假设 A 类清道夫受体 (SR-A) 是炎症的关键调节剂，可能会引导巨噬细胞极化，进而影响 MI 后的心肌细胞坏死。通过结扎左冠状动脉前降支，在野生型 (WT) 和 SR-A 缺陷型 (SR-A−/−) 小鼠中诱导 MI。与 WT 同窝小鼠相比，MI 后 SR-A−/− 小鼠的心脏功能恶化、心室扩张和纤维化均加剧。同时，免疫组织化学、流式细胞术、实时定量 PCR 和 ELISA 检测证明，SR-A−/− 小鼠中 M1 巨噬细胞极化增强，同时 M1 特征细胞因子的产生增加，包括白介素-1β (IL-1β)、IL-6 和肿瘤坏死因子-α (TNF-α)。此外，MI后SR-A−/−动物中激活的凋亡信号调节激酶1 (ASK1)/p38丝裂原激活蛋白激酶(MAPK)/核因子-κB (NF-κB)信号通路的激活显着升高。最重要的是，使用 SR-A+/+ 小鼠的骨髓移植部分恢复了 M1 巨噬细胞，并显着增强了 SR-A−/− 小鼠的左心室缩短分数。 SR-A 通过抑制巨噬细胞偏向 M1 表型的极化、减少 IL-1β、IL-6 和 TNF-α 的分泌以及抑制 ASK1/p38/NF-κB 信号通路来减弱 MI 诱导的心脏重塑。因此，SR-A可能对MI发挥保护作用，这可能代表治疗梗死后重构和随后的心力衰竭的新的介入靶点。
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.