Department of Pathology, Shanxi Medical University, Taiyuan, China.
Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China.
J Cell Mol Med. 2021 Sep;25(17):8464-8478. doi: 10.1111/jcmm.16807. Epub 2021 Jul 29.
Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that β -adrenergic receptor autoantibody (β -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that β -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by β -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that β -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by β -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by β -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by β -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by β -AA in cardiomyocytes. This study is the first time to confirm that β -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by β -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with β -AA-positive cardiac dysfunction.
心肌细胞自噬对于维持心脏功能至关重要。我们之前的研究发现，β-肾上腺素能受体自身抗体（β-AA）导致心肌自噬通量降低，从而导致心肌细胞死亡和心功能障碍。其他研究表明，β-AA 诱导 AMPK 磷酸化减少，而脂联素通过 AMPK 上调自噬通量。然而，尚不清楚脂联素是否通过上调 AMPK 磷酸化水平来改善β-AA 诱导的心肌自噬通量抑制。在本研究中，已经证实β-AA 在体内和体外均诱导 AMPK 磷酸化水平降低。此外，用 AMPK 抑制剂 Compound C 预处理心肌细胞可进一步降低β-AA 诱导的自噬通量。脂联素缺乏可加重β-AA 诱导的心肌 AMPK 磷酸化水平、自噬通量和心功能下降。进一步的，外源性脂联素可逆转β-AA 诱导的 AMPK 磷酸化水平和自噬通量下降，甚至减少心肌细胞死亡。而在用 Compound C 预处理后，脂联素处理并不能改善β-AA 诱导的自噬小体形成减少，但仍能改善自噬小体清除减少。本研究首次证实β-AA 可通过下调 AMPK 磷酸化水平抑制心肌自噬通量。脂联素可部分依赖 AMPK 改善β-AA 诱导的心肌自噬通量抑制，从而为治疗β-AA 阳性心功能障碍患者提供实验依据。
