期刊
CIRCULATION
卷 140, 期 3, 页码 225-239出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.118.038571
关键词
atherosclerosis; caveolae; extracellular matrix; fibronectins; inflammation; nitric oxide synthase type III; transcytosis
资金
- National Institutes of Health [R35HL135820, R01HL105945, R01HL 135012]
- American Heart Association [16EIA27550005, 16GRNT26420047, 17SDG33110002]
- Donna Dickenson-Sublett Award for the Advancement of Cardiovascular Research [SDG23000025]
- Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research, MicroRNA-based Therapeutic Strategies in Vascular Disease
- Plan Estatal de Investigacion y Tecnica y de Innovacion [SAF2015-70747-R]
- Heart and Stroke Foundation of Canada [G-16-00013521]
- Canada Research Chair
Background: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear. Methods: Triple-knockout mouse lacking expression of eNOS, Cav1, and Ldlr were generated to explore the role of NO production in Cav1-dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. Results: We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr(-/-)eNOS(-/-) mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flow-dependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. Conclusions: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.
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