Heart Failure Center, Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongrentiyuchangnan Rd, Beijing, 100020, China.
BMC Cardiovasc Disord. 2020 Jun 5;20(1):269. doi: 10.1186/s12872-020-01492-3.
Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that β1 adrenoceptor antibodies (β1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and β1AA, including the mechanism of β1AA leading to PPCM.
We extracted the β1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the β1 adrenoceptor to produce PPCM. We tested the effects of β1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1α was overexpressed to rescue the effect of β1AA on H9C2 cells.
We found that the extracted β1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after β1AA treatment. In addition, the effect of β1AA could be inhibited by atenolol, the antagonist of β1 adrenoceptors (β1AR) and imitated by isoprenaline, the agonist of β1AR. Furthermore, overexpression of PGC-1α in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by β1AA.
Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by β1AA inhibiting the PGC-1α-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the β1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.
围生期心肌病（PPCM）是一种危及生命的心脏病。然而，PPCM 的病因和发病机制尚不清楚。先前的研究发现，β1 肾上腺素能受体抗体（β1AA）可能参与 PPCM 的发生。在本研究中，我们确定了 PPCM 与β1AA 之间的潜在关系，包括β1AA 导致 PPCM 的机制。
我们从注射β1 肾上腺素能受体抗原肽段的产后 Wistar 大鼠中提取β1AA，以产生 PPCM。我们通过 CCK-8、LDH、TUNEL、SA-ELISA、qRT-PCR 和 Western blot 方法检测β1AA 对 H9C2 细胞系的影响。此外，过表达 PGC-1α 以挽救β1AA 对 H9C2 细胞的作用。
我们发现提取的β1AA 诱导 H9C2 细胞系心肌细胞凋亡。此外，过氧化物酶体增殖物激活受体 γ 共激活因子-1α（PGC-1α）的表达，作为线粒体代谢的主要调节因子，及其下游转录血管内皮生长因子（VEGF）在β1AA 处理后在 H9C2 细胞中降低。此外，β1AA 的作用可以被β1 肾上腺素能受体（β1AR）拮抗剂阿替洛尔抑制，并被β1AR 激动剂异丙肾上腺素模拟。此外，在 H9C2 细胞中过表达 PGC-1α 可挽救β1AA 诱导的细胞凋亡和 VEGF 的抑制表达。
我们的结果表明，β1AA 抑制 PGC-1α 相关通路导致心肌细胞凋亡引起的 PPCM 症状会损害线粒体能量代谢。因此，我们的结果揭示了β1AA 通路在 PPCM 发病机制中的一个未知作用，并为 PPCM 的治疗提供了一个新的潜在靶点。
