Gaojian Huang1,2, Zhilei Cong3, Xiaoyan Wang4, Yanggang Yuan5, Renjie Xu1, Zhaoyang Lu1,6, Xuelian Wang1,6, Jia Qi1,4. 1. Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 2. Department of Hypertension and Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. 3. Department of Emergency, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China. 4. Department of Cardiology, Affiliated Hospital of Jiangnan University, Wuxi 214000, China. 5. Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. 6. Department of Gerontology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Abstract
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 role 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, while 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 role 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 hypertensivemice. 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, while 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Stephanie M Cicalese; Josiane Fernandes da Silva; Fernanda Priviero; R Clinton Webb; Satoru Eguchi; Rita C Tostes Journal: Circ Res Date: 2021-04-01 Impact factor: 17.367
Authors: Siarhei A Dabravolski; Vasily N Sukhorukov; Vladislav A Kalmykov; Nikolay A Orekhov; Andrey V Grechko; Alexander N Orekhov Journal: Int J Mol Sci Date: 2022-01-07 Impact factor: 5.923