Zhan Enbo, Cao Wei, Fan Xiaoying, Zhang Ruoxi, Du Hongwei, Xu Yousheng, Li Lili, Dong Nana, Li Shaojun
Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University Harbin, Heilongjiang, P. R. China.
Am J Transl Res. 2020 Dec 15;12(12):7995-8006. eCollection 2020.
Adora2B (adenosine receptor 2B) has been reported as one of the key modulators during cardiac remodeling after acute myocardial infarction (AMI). However, the molecular mechanism involved has not been well investigated. Thus, our study aims to investigate whether Adora2B contributes to cardiac remodeling after AMI and its underlying mechanisms. Adenovirus harboring Adora2B or shAdora2B was injected in the border zone in a mouse model of AMI experimentally produced by permanent ligation of left anterior descending (LAD) coronary artery. Decreased Adora2B expression protected the cardiomyocytes from MI-induced autophagic flux obstacle, improved cardiac function, and reduced fibrosis after MI. Adora2B downregulation attenuated the accumulation of LC3-II and p62, which are autophagy substrate proteins. An adenovirus containing mRFP-GFP-LC3 showed that decreased expression of Adora2B restored the autophagic flux by enhancing autophagosome conversion to autophagolysosome. Also, Adora2B knockdown improved cardiomyocytes' survival and protected mitochondrial function of cardiomyocytes insulted with hypoxia. Notably, the effect of Adora2B on autophagy flux and cardiomyocyte protection could be mitigated by autophagy inhibitor chloroquine. Our results demonstrate that decreased expression of Adora2B protected cardiomyocytes from impaired autophagy flux induced by MI. Modulation Adora2B expression plays a significant role in blunting the worsening of heart function and reducing scar formation, suggesting therapeutic potential by targeting Adora2B in AMI for the infarct healing.
据报道，A2B 型腺苷受体（Adora2B）是急性心肌梗死（AMI）后心脏重塑过程中的关键调节因子之一。然而，其中涉及的分子机制尚未得到充分研究。因此，我们的研究旨在探讨 Adora2B 是否参与 AMI 后的心脏重塑及其潜在机制。将携带 Adora2B 或 shAdora2B 的腺病毒注射到通过永久性结扎左冠状动脉前降支（LAD）实验性制造的 AMI 小鼠模型的边缘区。Adora2B 表达降低可保护心肌细胞免受心肌梗死诱导的自噬通量障碍，改善心脏功能，并减少心肌梗死后的纤维化。Adora2B 下调减弱了自噬底物蛋白 LC3-II 和 p62 的积累。含有 mRFP-GFP-LC3 的腺病毒显示，Adora2B 表达降低通过增强自噬体向自噬溶酶体的转化来恢复自噬通量。此外，敲低 Adora2B 可提高心肌细胞的存活率，并保护受缺氧损伤的心肌细胞的线粒体功能。值得注意的是，自噬抑制剂氯喹可减轻 Adora2B 对自噬通量和心肌细胞保护的作用。我们的结果表明，Adora2B 表达降低可保护心肌细胞免受心肌梗死诱导的自噬通量受损。调节 Adora2B 表达在减轻心脏功能恶化和减少瘢痕形成方面发挥着重要作用，这表明在 AMI 中靶向 Adora2B 促进梗死愈合具有治疗潜力。
