期刊
CARDIOVASCULAR RESEARCH
卷 116, 期 5, 页码 1071-1084出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz194
关键词
Dynamin related protein 1; Adventitial fibroblasts; Mitochondrial fission; Hypertension
资金
- Chinese Natural Science Foundation [81670628, 11574210, 11374213, 81302768, 81603099]
- Natural Science Foundation of Shanghai [17ZR1418300]
- Shanghai Municipal Commission of Health and Family Planning [20174Y0195]
- Shanghai `Rising Stars of Medical Talent' Youth Development Program
- China Postdoctoral Science Foundation [2017M610259]
- China Scholarship Council (CSC) [201608320124]
- Clinic Research Center of Jiangsu Province [BL2014080]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institution
Aims Adventitial remodelling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signalling and transcriptional pathways in vascular smooth muscle cells; however, little is known about its rote on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin (CN), a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodelling in AngII-induced hypertensive mice. Methods and results In primary mouse AFs, we found that CN-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial reactive oxygen species production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and CN in AFs, white HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the CN-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodelling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by CN/Drp1 signalling pathways. Conclusions Our study suggests that CN/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodelling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodelling-related diseases. [GRAPHICS] .
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