Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis

Antioxidants

卷:11

Antonio Zorzano¹  Clément Tétaud²  Linda Grimaud²  Daniel Henrion²  Vincent Procaccio²  Benoit Legouriellec²  Emilie Vessieres²  Coralyne Proux²  Guy Lenaers²  Anne-Laure Guihot²  Jade Aurrière²  Pascal Reynier²  Laurent Loufrani²  Jordan Rivron²  Ahmad Chehaitly²  Françoise Joubaud³ 

[1] Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10–12, 08028 Barcelona, Spain;

[2] MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France;

[3] University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;

关键词: mitochondrial fusion;    blood flow;    shear stress;    arteries;    endothelial cell;    atherosclerosis;   

DOI  :  10.3390/antiox11061078

来源: DOAJ

【 摘 要 】

Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1^+/− mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H₂O₂ production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr^−/--Opa1^+/- and in Ldlr^−/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.

【 授权许可】

Unknown