Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis.
The accumulation of LDL-derived cholesterol in the artery wall is the initiating event that causes atherosclerosis. However, the mechanisms that lead to the initiation of atherosclerosis are still poorly understood. Here, by using endothelial cell-specific transgenesis of the caveolin-1 (Cav-1) gene in mice, we show the critical role of Cav-1 in promoting atherogenesis. Mice were generated lacking Cav-1 and apoE but expressing endothelial-specific Cav-1 in the double knockout background. Genetic ablation of Cav-1 on an apoE knockout background inhibits the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promotes lesion expansion. Mechanistically, the loss of Cav-1 reduces LDL infiltration into the artery wall, promotes nitric oxide production, and reduces the expression of leukocyte adhesion molecules, effects completely reversed in transgenic mice. In summary, this unique model provides physiological evidence supporting the important role of endothelial Cav-1 expression in regulating the entry of LDL into the vessel wall and the initiation of atherosclerosis.
Fernández-Hernando
Carlos
C
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Yu
Jun
J
Suárez
Yajaira
Y
Rahner
Christoph
C
Dávalos
Alberto
A
Lasunción
Miguel A
MA
Sessa
William C
WC
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism
D001057:Apolipoproteins E; D051242:Caveolin 1; D008078:Cholesterol, LDL; D009569:Nitric Oxide