RT Journal Article
SR Electronic
T1 Attenuation by Statins of Membrane Raft-Redox Signaling in Coronary Arterial Endothelium
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.112.201442
DO 10.1124/jpet.112.201442
A1 Yu-Miao Wei
A1 Xiang Li
A1 Jing Xiong
A1 Justine M. Abais
A1 Min Xia
A1 Krishna M. Boini
A1 Yang Zhang
A1 Pin-Lan Li
YR 2013
UL http://jpet.aspetjournals.org/content/early/2013/02/22/jpet.112.201442.abstract
AB Membrane raft (MR)-redox signaling platforms associated with NADPH oxidase are involved in coronary endothelial dysfunction. Here, we studied whether statins interfere with the formation of MR-redox signaling platforms to protect the coronary arterial endothelium from oxidized low-density lipoprotein (OxLDL)-induced injury and from acute hypercholesterolemia. In cultured human coronary arterial endothelial cells (HCAECs), confocal microscopy detected the formation of a MRs clustering when they were exposed to OxLDL, and such MR platform formation was inhibited markedly by statins including pravastatin and simvastatin. In these MR clusters, NADPH oxidase subunits, gp91phox and p47phox were aggregated, which was markedly blocked by both statins. Besides that, co-localization of acid sphingomyelinase (ASM) and ceramide was induced by OxLDL, which was blocked by statins. Electron spin resonance spectrometry showed that OxLDL-induced superoxide (O2.-) production in the MR fractions was substantially reduced by statins. In coronary artery intima of mice with acute hypercholesterolemia, confocal microscopy demonstrated a co-localization of gp91phox, p47phox, ASM or ceramide within MR clusters. Such co-localization was rarely observed in the arteries of normal mice or significantly reduced by pretreatment of hypercholesterolemic mice with statins. Further, O2.- production in situ was 3 folds higher in the coronary arteries from hypercholesterolemic mice than normal mice, and such increase was inhibited by statins. Our results indicate that blockade of MR redox signaling platform formation in endothelial cell membrane may be another important therapeutic mechanism of statins in preventing endothelial injury and atherosclerosis, which may be associated with their direct action on membrane cholesterol structure and function.