The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
Signal Transduct Target Ther. 2022 Aug 1;7(1):259. doi: 10.1038/s41392-022-01054-3.
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17 control, A17 control, ADAM17 diabetic and A17 diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17 and ADAM17 diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
血管紧张素转换酶 2（ACE2）已被证明可减轻糖尿病心肌病（DCM），但它被发现是解整合素金属蛋白酶 17（ADAM17）的底物。然而，ADAM17 是否在 DCM 的发病机制和干预中起作用尚不清楚。在这项研究中，我们创建了心肌细胞特异性敲除 ADAM17（A17）的小鼠，并评估了 ADAM17 对照组、A17 对照组、ADAM17 糖尿病组和 A17 糖尿病组的左心室尺寸、功能、病理和分子生物学。我们使用分化的 H9c2 细胞和新生大鼠心肌细胞（NRCMs）来探索 ADAM17 对 DCM 影响的分子机制。结果表明，糖尿病小鼠心肌中 ADAM17 的蛋白表达和活性上调，而 ACE2 的蛋白表达下调。心肌细胞特异性敲除 ADAM17 减轻了 DCM 小鼠的心脏纤维化和心肌细胞凋亡，并改善了心脏功能障碍。生物信息学分析检测到代谢途径中表达差异的许多基因，特别是 AMPK 信号通路。A17 和 ADAM17 糖尿病小鼠心脏之间差异表达的基因可能涉及激活的 AMPK 通路、增加自噬体形成和改善自噬流，从而减少心肌细胞的凋亡反应。此外，缺氧诱导因子-1α（HIF-1α）可能作为 ADAM17 上调的上游介质，ADAM17 可能通过α1 A-肾上腺素能受体（ADRA1A）影响 AMPK 信号。这些结果表明，DCM 中 ADAM17 的活性和 ACE2 的脱落增强，而心肌细胞特异性 ADAM17 敲除则逆转了这种情况。因此，抑制 ADAM17 可能为治疗 DCM 提供一种有前途的方法。
