High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
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 understood. 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.
Yuhanna
I S
IS
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Zhu
Y
Y
Cox
B E
BE
Hahner
L D
LD
Osborne-Lawrence
S
S
Lu
P
P
Marcel
Y L
YL
Anderson
R G
RG
Mendelsohn
M E
ME
Hobbs
H H
HH
Shaul
P W
PW
D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016466:CHO Cells; D002461:Cell Line, Transformed; D006224:Cricetinae; D017931:DNA Primers; D004789:Enzyme Activation; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B; D012756:Sheep
D018955:CD36 Antigens; D017931:DNA Primers; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III