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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gordon, D.J. & Rifkind, B.M. High-density lipoprotein–the clinical implications of recent studies. N. Engl. J. Med. 321, 1311–1316 (1989).
Krieger, M. The “best” of cholesterols, the “worst” of cholesterols: A tale of two receptors. Proc. Soc. Exp. Biol. Med. 95, 4077–4080 (1998).
Harrison, D.G. Endothelial dysfunction in atherosclerosis. Basic Res. Cardiol. 89, 87–102 (1994).
Cohen, R.A. The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog. Cardiovasc. Dis. 38, 105–128 (1995).
Lefer, A.M. & Ma, X.L. Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium. Arterioscler. Thromb. 13, 771–776 (1993).
Cayatte, A.J., Palacino, J.J., Horten, K. & Cohen, R.A. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler. Thromb. 14, 753–759 (1994).
Ignarro, L.J., Cirino, G., Casini, A. & Napoli, C. Nitric oxide as a signaling molecule in the vascular system: an overview. J. Cardiovasc. Pharmacol. 34, 879–886 (1999).
Shaul, P.W. & Anderson, R.G.W. Role of plasmalemmal caveolae in signal transduction. Am. J. Physiol. Lung Cell. Mol. Physiol. 275, L843–L851 (1998).
Zannis, V. I., Kardassis, D & Zannis, E.E. Genetic mutations affecting human lipoproteins, their receptors, and their enzymes. in Advances in Human Genetics (eds. Harris, H. & Hirschhorn, K.) 145–319 (Plenum, New York, 1993).
Kingsley, D.M. & Krieger, M. Receptor-mediated endocytosis of low density lipoprotein: somatic cell mutants define multiple genes required for expression of surface-receptor activity. Proc. Natl. Acad. Sci. USA 81, 5454–5458 (1984).
Stangl, H., Cao, G., Wyne, K.W. & Hobbs, H.H. Scavenger receptor, class B, type I-dependent stimulation of cholesterol esterification by high density lipoproteins, low density lipoproteins, and nonlipoprotein cholesterol. J. Biol. Chem. 273, 31002–31008 (1998).
Babitt, J. et al. Murine SR-BI, a high density lipoprotein receptor that mediates selective lipid uptake, is N-glycosylated and fatty acylated and colocalizes with plasma membrane caveolae. J. Biol. Chem. 272, 13242–13249 (1997).
Uittenbogaard, A. et al. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric oxide synthase localization and activation in caveolae. J. Biol. Chem. 275, 11278–11283 (2000).
Chambliss, K.L. et al. ER–α and eNOS are organized into a functional signaling module in caveolae. Circ. Res. 87, E44–E52 (2000).
Liadaki, K.N. et al. Binding of high density lipoprotein (HDL) and discoidal reconstituted HDL to the HDL receptor scavenger receptor class B type I. J. Biol. Chem. 275, 21262–21271 (2000).
Rigotti, A. et al. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc. Natl. Acad. Sci. USA 94, 12610–12615 (1997).
Fidge, N.H. High density lipoprotein receptors, binding proteins, and ligands. J. Lipid Res. 40, 187–201 (1999).
Trigatti, B. et al. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc. Natl. Acad. Sci. USA 96, 9322–9327 (1999).
Jolley, C.D., Woollett, L.A., Turley, S.D. & Dietschy, J.M. Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoproteinor apolipoprotein A-I concentration. J. Lipid Res. 39, 2143–2149 (1998).
Xia, P., Vadas, M.A., Rye, K.-A., Barter, P.J. & Gamble, J.R. High density lipoproteins interrupt the sphingosine kinase pathway. J. Biol. Chem. 274, 33143–33147 (1999).
Ross, R. Atherosclerosis- an inflammatory disease. New Engl. J. Med. 340, 115–126 (1999).
Acton, S. et al. Identification of scavenger receptor SR-BI as high density lipoprotein receptor. Science 271, 518–520 (1996).
Stangl, H., Hyatt, M. & Hobbs, H.H. Transport of lipids from high and low density lipoproteins via scavenger receptor-BI. J. Biol. Chem. 274, 32692–32698 (1999).
Swarnakar, S., Temel, R.E., Connelly, M.A., Azhar, S. & Williams, D.L. Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester. J. Biol. Chem. 274, 29733–29739 (1999).
Kellner-Weibel, G. et al. Expression of scavenger receptor BI in COS-7 cells alters cholesterol content and distribution. Biochemistry 39, 221–229 (2000).
Reaven, E., Leers-Sucheta, S., Nomoto, A. & Azhar, S. Expression of scavenger receptor class B type 1 promotes microvillar channel formation and selective cholesteryl ester transport in a heterologous reconstituted system. Proc. Natl. Acad. Sci. USA 98, 1613–1618 (2001)
Ikemoto, M. et al. Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I. Proc. Natl. Acad. Sci. USA 97, 6538–6543 (2000).
Pace, M.C. et al. Establishment of an immortalized fetal intrapulmonary artery endothelial cell line. Am. J. Physiol. Lung Cell. Mol. Physiol. 277, L106–L112 (1999).
Shaul, P.W. et al. Acylation targets endothelial nitric oxide synthase to plasmalemmal caveolae. J. Biol. Chem. 271, 6518–6522 (1996).
Bergeron, J. et al. Characterization of human apolipoprotein A-I expressed in Escherichia coli. Biochim. Biophys. Acta 1344, 139–152 (1997).
Weisweiler, P. Isolation and quantitation of apolipoproteins A-I and A-II from human high -density lipoproteins by fast-protein liquid chromatography. Clinica. Chimica. Acta. 169, 249–254 (1987).
Jun, S.S., Chen, Z., Pace, M.C. & Shaul, P.W. Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium. J. Clin. Invest. 102, 176–183 (1998).
Zhu, Y., Lu, P. & Mendelsohn, M.E. Basal release of nitric oxide in mouse aortic rings is inhibited by antiestrogens but not affected by estrogen receptor beta. Circulation 100, I–219 (1999).
Shaul, P.W., Farrar, M.A. & Zellers, T.M. Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. Am. J. Physiol. Heart Circ. Physiol. 262, H355–H364 (1992).
Hayashi, T., Fukuto, J.M., Ignarro, L.J. & Chaudhuri, G. Basal release of nitric oxide from aortic rings is greater in female rabbits than male rabbits: implications for atherosclerosis. Proc. Natl. Acad. Sci. USA 89, 11259–11263 (1992).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/89986
This article is cited by
-
LDL Transcytosis by the Arterial Endothelium—Atherosclerosis by a Thousand Cuts?
Current Atherosclerosis Reports (2023)
-
High-Density Lipoprotein Is Associated with Leukoaraiosis Severity in Patients with Acute Ischemic Stroke
Neurotoxicity Research (2022)
-
Progression to Cirrhosis Leads to Improvement in Atherogenic Milieu
Digestive Diseases and Sciences (2021)
-
High-density lipoprotein-mediated cardioprotection in heart failure
Heart Failure Reviews (2021)
-
High-density lipoprotein cholesterol concentration and acute kidney injury after noncardiac surgery
BMC Nephrology (2020)