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作者

Jing Cheng, Fei Xue, Cheng Cheng, Wenhai Sui, Meng Zhang, Lei Qiao, Jing Ma, Xiaoping Ji, Wenqiang Chen, Xiao Yu, Bo Xi, Feng Xu, Guohai Su, Yuxia Zhao, Panpan Hao, Yun Zhang, Cheng Zhang

作者单位

Affiliations ¹ 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, China. ² Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. ³ Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. ⁴ Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China. ⁵ Department of Emergency Medicine, Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China. ⁶ Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China. ⁷ Department of Traditional Chinese Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

刊名

Frontiers in pharmacology

年份

2022

卷号

Vol.13

页码

997916

ISSN

1663-9812

关键词

ACE2 ADAM17 TGF-β1/Smad3 signaling cardiac fibrosis myofibroblast transformation

摘要

A disintegrin and metalloprotease domain family protein 17 is a new member of renin-angiotensin system but its role in the pathogenesis of diabetic cardiomyopathy is obscure. To test the hypothesis that ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation in diabetic mice, ADAM17 gene was knocked down and overexpressed by means of adenovirus-mediated short-hairpin RNA and adenovirus vector carrying AD...更多

A disintegrin and metalloprotease domain family protein 17 is a new member of renin-angiotensin system but its role in the pathogenesis of diabetic cardiomyopathy is obscure. To test the hypothesis that ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation in diabetic mice, ADAM17 gene was knocked down and overexpressed by means of adenovirus-mediated short-hairpin RNA and adenovirus vector carrying ADAM17 cDNA, respectively, in a mouse model of DCM. Two-dimensional and Doppler echocardiography, histopathology and immunohistochemistry were performed in all mice and in vitro experiments conducted in primary cardiofibroblasts. The results showed that ADAM17 knockdown ameliorated while ADAM17 overexpression worsened cardiac dysfunction and cardiac fibrosis in diabetic mice. In addition, ADAM17 knockdown increased ACE2 while reduced AT1R expression in diabetic hearts. Mechanistically, ADAM17 knockdown decreased while ADAM17 overexpression increased cardiac fibroblast-to-myofibroblast transformation through regulation of TGF-β1/Smad3 signaling pathway. In conclusion, ADAM17 knockdown attenuates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation through TGF-β1/Smad3 signaling pathway in diabetic mice. Targeting ADAM17 may provide a promising approach to the prevention and treatment of cardiac fibrosis in DCM.收起

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