巨噬细胞支链氨基酸代谢障碍致M1/M2极化失衡参与心梗后炎症反应与病理性重构

Cardiac inflammation and remodeling cause post-myocardial infarction (MI) heart failure. We have previously demonstrated that branched chain amino acids (BCAA) catabolic disorders exacerbate post-MI cardiac inflammation and remodeling. However, the underlying mechanisms remain unknown. Here we found that β-adrenergic system overactivation caused obvious defects of BCAA catabolism in macrophages following MI. With severe BCAA catabolic defects, PP2CM deficient macrophages showed impaired IL-4 induced M2 phenotype but enhanced LPS/IFNγ-induced M1 phenotype. Furthermore, the expression levels and transcriptional activities of PPARγ were significantly decreased in PP2CM deficient macrophages. Collectively, these findings lead to a strong speculation that macrophage BCAA catabolism might affect post-MI cardiac inflammation and remodeling via regulating M1/M2 homeostasis in a PPARγ-dependent manner. Utilizing macrophage specific PP2CM knockout (Lyz2-PP2CMfl/fl) mice, the project aims to clarify the regulatory role of BCAA catabolism in macrophage polarization and post-MI cardiac inflammation and remodeling.

心肌梗死(MI)后心脏炎症反应与病理性重构是导致心衰的关键原因。申请人前期证实支链氨基酸(BCAA)代谢障碍加重MI后心脏炎症反应与病理性重构，但其机制尚未阐明。我们预实验结果发现交感-肾上腺素系统释放的儿茶酚胺可导致巨噬细胞BCAA代谢障碍，造成巨噬细胞促炎M1型极化增强而抗炎M2型极化缺陷，其可能机制是BCAA代谢障碍导致的PPARγ信号受损。因此，本课题拟利用已构建的巨噬细胞特异性BCAA代谢障碍(Lyz2-PP2CMfl/fl)小鼠，结合整体动物与离体细胞实验，深入阐明巨噬细胞BCAA代谢对其极化的影响及下游分子机制，并明确巨噬细胞BCAA代谢障碍致M1/M2极化失衡在MI后心脏炎症反应与病理性重构中的作用。本项目的实施可望从氨基酸代谢角度揭示巨噬细胞极化的新调控机制，并为临床防治MI后心脏炎症反应与病理性重构提供新思路与新靶点。

本项目重点关注支链氨基酸（BCAA）代谢障碍与缺血心肌损伤的关系。在本项目资助下，本项目组发现支链氨基酸代谢调节心肌细胞代谢影响心肌缺血易损性：BCAA可抑制心肌细胞葡萄糖氧化，增加脂肪酸氧化和葡萄糖酵解。BCAA可增加脂毒性产物蓄积并加重离体心肌细胞缺氧/复氧（H/R）损伤，上述作用可被脂肪酸氧化抑制剂Etomoxir逆转。口服BCAA可加重小鼠心肌IR损伤，并导致脂肪酸氧化相关毒性产物蓄积，上述负性作用可被Etomoxir逆转。BCAA/BCKA可显著上调PPARα表达，抑制或敲低PPARα可阻断BCAA对脂肪酸氧化酶表达的促进作用。我们进一步发现BCAA当中的缬氨酸和亮氨酸及其下游BCKA产物，而不是异亮氨酸，可以通过抑制GCN2-ATF6信号通路上调PPARα表达。BCAA代谢障碍小鼠心脏IR损伤加重，而敲低PPARα可显著减轻其缺血-再灌注损伤。本项目揭示了BCAA代谢障碍加重缺血心肌损伤的作用并阐明了下游分子机制，为靶向BCAA代谢障碍防治缺血心肌损伤提供了理论基础与实验证据。