A novel ligand-independent apoptotic pathway induced by scavenger receptor class B, type I and suppressed by endothelial nitric-oxide synthase and high density lipoprotein.
Scavenger receptor class B, type I (SR-BI)/ApoE double null mice develop severe atherosclerosis within 4 weeks, whereas ApoE null mice take several months to develop the disease, indicating that SR-BI plays a pivotal role in atherosclerosis. Importantly, SR-BI/ApoE double null mice have lower plasma cholesterol levels than ApoE null mice, suggesting involvement of a non-lipids mechanism. In the present study, we revealed a novel ligand-independent apoptotic pathway induced by SR-BI, and regulated by endothelial nitric-oxide synthase (eNOS) and high density lipoprotein (HDL). SR-BI significantly induces apoptosis in three independent cell systems. In contrast to known ligand-dependent apoptotic pathways, SR-BI-induced apoptosis is ligand-independent. We further showed that SR-BI-induced apoptosis is suppressed by eNOS and HDL. By using a single site mutation, we demonstrated that SR-BI induces apoptosis through a highly conserved CXXS redox motif. We finally demonstrated that SR-BI-induced apoptosis is via the caspase-8 pathway. We hypothesize that in healthy cells, the SR-BI apoptotic pathway is turned off by eNOS and HDL which prevents inappropriate apoptotic damage to the vascular wall. When HDL levels are low, oxidative stress causes the relocation of eNOS away from caveolae, which turns on SR-BI-induced apoptosis and rapidly clears damaged cells to prevent further inflammatory damage to neighboring cells. The current studies offer a new paradigm in which to study the non-cholesterol effects of SR-BI, HDL, and eNOS on the development of atherosclerosis and potentially other cardiovascular diseases.
Li
Xiang-An
XA
Department of Pediatrics, University of Kentucky Medical School, Lexington, Kentucky 40536-0230, USA.
Guo
Ling
L
Dressman
James L
JL
Asmis
Reto
R
Smart
Eric J
EJ
D020816:Amino Acid Motifs; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D017209:Apoptosis; D001161:Arteriosclerosis / Q000378:metabolism; D001665:Binding Sites; D018955:CD36 Antigens; D016466:CHO Cells; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D008024:Ligands; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008858:Microscopy, Phase-Contrast; D008954:Models, Biological; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013997:Time Factors
D001057:Apolipoproteins E; D018955:CD36 Antigens; D018076:DNA, Complementary; D008024:Ligands; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse