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Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2022-08-01 , DOI: 10.1038/s41392-022-01054-3
Fei Xue 1 , Jing Cheng 1, 2 , Yanping Liu 1 , Cheng Cheng 1 , Meng Zhang 1, 3 , Wenhai Sui 1 , Wenqiang Chen 1 , Panpan Hao 1 , Yun Zhang 1, 3 , Cheng Zhang 1, 3
Affiliation  

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 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO 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 A17α-MHCKO and ADAM17fl/fl 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.



中文翻译:

心肌细胞特异性敲除 ADAM17 可改善小鼠糖尿病性心肌病的左心室重塑和功能

血管紧张素转换酶 2 (ACE2) 已被证明对减轻糖尿病心肌病 (DCM) 有益,但已被发现是去整合素和金属蛋白酶蛋白 17 (ADAM17) 的底物。然而,ADAM17是否在DCM的发病机制和干预中发挥作用尚不清楚。在这项研究中,我们创建了 ADAM17 (A17 α-MHCKO ) 小鼠的心肌细胞特异性敲除,并在 ADAM17 fl/fl对照、A17 α-MHCKO对照、ADAM17 fl/fl中评估了左心室尺寸、功能、病理学和分子生物学糖尿病和 A17 α-MHCKO糖尿病小鼠。分化的 H9c2 细胞和新生大鼠心肌细胞 (NRCM) 均用于探索 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 可减轻 DCM 小鼠的心脏纤维化和心肌细胞凋亡,并改善心功能不全。生物信息学分析检测到许多富含代谢途径的基因,特别是 AMPK 信号通路,在 A17 α-MHCKO和 ADAM17 fl/fl的心脏之间存在差异表达糖尿病小鼠。该机制可能涉及激活 AMPK 通路、增加自噬体形成和改善自噬通量,从而降低心肌细胞的凋亡反应。此外,缺氧诱导因子-1α (HIF-1α) 可能作为上调 ADAM17 的上游介质,ADAM17 可能通过α1 A-肾上腺素能受体 (ADRA1A) 影响 AMPK 信号传导。这些结果表明,在 DCM 中 ADAM17 活性和 ACE2 脱落增强,这被心肌细胞特异性 ADAM17 敲除所逆转。因此,抑制 ADAM17 可能为治疗 DCM 提供有希望的方法。

更新日期:2022-08-01
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