Targeting HSP90 attenuates angiotensin II-induced adventitial remodelling via suppression of mitochondrial fission.

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.

• Authors: Gaojian Huang, Zhilei Cong, Xiaoyan Wang, Yanggang Yuan, Renjie Xu, Zhaoyang Lu, Xuelian Wang, Jia Qi
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 116 Issue 5 Pg. 1071-1084 (04 01 2020) ISSN: 1755-3245 [Electronic] England
• PMID: 31346611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Reactive Oxygen Species
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• Angiotensin II
• Calcineurin
• Dnm1l protein, mouse
• Dynamins

Topics

• Adventitia (drug effects, metabolism, pathology)
• Angiotensin II
• Animals
• Aorta, Thoracic (drug effects, metabolism, pathology)
• Benzoquinones (pharmacology)
• Calcineurin (metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Dynamins (metabolism)
• Fibroblasts (drug effects, metabolism, pathology)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Hypertension (chemically induced, drug therapy, metabolism, pathology)
• Lactams, Macrocyclic (pharmacology)
• Male
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Dynamics (drug effects)
• Molecular Targeted Therapy
• Phenotype
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Vascular Remodeling (drug effects)