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High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase

Nature Medicine volume 7, pages 853–857 (2001)Cite this article

Abstract

Atherosclerosis is the primary cause of cardiovascular disease, and the risk for atherosclerosis is inversely proportional to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood1,2. Here we show that HDL stimulates endothelial nitric oxide synthase (eNOS) in cultured endothelial cells. In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein. Heterologous expression experiments in Chinese hamster ovary cells reveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cell caveolae where SR-BI and eNOS are colocalized, and the response in isolated plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not by antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide–dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I.

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Figure 1: HDL activates eNOS in endothelial cells.
Figure 2: eNOS activation by HDL requires SR-BI and occurs in endothelial caveolae.
Figure 3: HDL enhances endothelial NO production in aortae from wild-type mice, but not in aortae from homozygous SR-BI–null mutant mice.

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Acknowledgements

We thank M. Dixon for preparing this manuscript. This work was supported by National Institutes of Health grants HL58888, HL53546 and HD30276 (to P.W.S.), NL20948 (to H.H.H.), GM52016 (to R.G.W.A.), and HL56069 and HL59953 (to M.E.M.). The project was also supported in part by a Group Grant from CIHR, GR11471 (to Y.L.M.), the Lowe Foundation, the Reynolds Foundation and the Perot Family Foundation.

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Authors and Affiliations

  1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ivan S. Yuhanna, Blair E. Cox, Lisa D. Hahner, Sherri Osborne-Lawrence & Philip W. Shaul

  2. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Helen H. Hobbs

  3. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Richard G.W. Anderson

  4. Molecular Cardiology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA

    Yan Zhu, Ping Lu & Michael E. Mendelsohn

  5. Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    Yves L. Marcel

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Correspondence to Philip W. Shaul.

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Yuhanna, I., Zhu, Y., Cox, B. et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med 7, 853–857 (2001). https://doi.org/10.1038/89986

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