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Circulation. 2019 Jul 16;140(3):225-239. doi: 10.1161/CIRCULATIONAHA.118.038571. Epub 2019 Jun 3.

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation.

Author information

1
Vascular Biology and Therapeutics Program (C.M.R., X.Z., N.R., B.A., J.R.K., V.U., Y.S., W.C.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.
2
Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology (C.M.R., X.Z., N.R., B.A., Y.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.
3
Cardiovascular Research Center, Department of Internal Medicine and Cell Biology (C.B., M.A.S.), Yale University School of Medicine, New Haven, CT.
4
Keenan Research Centre and Departments of Laboratory Medicine and Pathobiology, Biochemistry and Medicine, University of Toronto, ON, Canada (M.G.S., W.L.L.).
5
Department of Cell Biology (X.L.), Yale University School of Medicine, New Haven, CT.
6
Center for System Biology, Massachusetts General Hospital and Harvard Medical School, Boston (S.H., F.K.S.).
7
Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (C.S.L.).
8
Section of Nephrology (H.V.), Yale University School of Medicine, New Haven, CT.
9
Departments of Cell Biology and Biomedical Engineering (G.L., G.T.), Yale University School of Medicine, New Haven, CT.
10
Department of Surgery (G.L., G.T.), Yale University School of Medicine, New Haven, CT.
11
Department of Cell Biology (M.A.S.), Yale University School of Medicine, New Haven, CT.
12
Departamento de Bioquímica-Investigación, Hospital Ramón y Cajal, IRyCIS, Madrid, Spain (M.A.L.).
13
CIBER de Fisiopatología de la Obesidad y Nutrición, ISCIII, Madrid, Spain (M.A.L.).
14
Department of Pharmacology (W.C.S.), Yale University School of Medicine, New Haven, CT.

Abstract

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.

KEYWORDS:

atherosclerosis; caveolae; extracellular matrix; fibronectins; inflammation; nitric oxide synthase type III; transcytosis

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