Cholesterol increases adhesion of monocytes to endothelium by moving adhesion molecules out of caveolae.
Caveolae and its structural protein caveolin-1 (Cav-1) are abundant in vascular endothelial cells (ECs). We examined whether caveolae are involved in monocyte adhesion to ECs responding to a synergy of hypercholesterolemia and inflammation. Treating human umbilical vein ECs with cholesterol enhanced endotoxin lipopolysaccharide (LPS)-induced monocyte adhesion. Use of isolated caveolae-enriched membranes revealed that cell adhesion molecules (CAMs), including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), co-localized with Cav-1 in caveolae. LPS upregulated CAMs expression and increased the co-localization. Cholesterol exposure decreased the level of CAMs in the caveolae. Co-immunoprecipitation and confocal microscopy revealed that ICAM-1 interacted with Cav-1. Electron microscopy showed that ICAM-1 was mainly located in caveolae. Cholesterol exposure decreased this interaction and drove ICAM-1 out of caveolae. Knockdown of Cav-1 reduced the synergistic effects of cholesterol and inflammation. In vivo, ICAM-1 and Cav-1 co-localization was lower in the aortic endothelium of ApoE(-)(/)(-) mice than in that of wild-type controls. Cav-1 negatively regulates monocyte adhesion by the co-localization of CAMs in caveolae, which is disturbed by cholesterol. Thus, our study suggests a molecular basis underlying the synergistic effects of hypercholesterolemia and inflammation in atherogenesis.
Fu
Chenglai
C
Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Peking University Health Science Center, Beijing 100091, China.
He
Jinlong
J
Li
Chenghong
C
Shyy
John Y-J
JY
Zhu
Yi
Y
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002417:Cattle; D021941:Caveolae / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D051242:Caveolin 1; D008070:Lipopolysaccharides; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol