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Enhanced Membrane Raft‐Redox Signaling Associated with NADPH Oxidase in Coronary Arterial Endothelium during Hypercholesterolemia
Author(s) -
Wei Yu-Miao,
Zhang Yang,
Boini Krishna M.,
Li Pin-Lan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.681.4
Subject(s) - nadph oxidase , chemistry , ceramide , p22phox , redox , medicine , endocrinology , pharmacology , sphingomyelin , oxidative stress , cholesterol , biochemistry , apoptosis , organic chemistry
Membrane raft (MR)‐redox signaling platforms associated with NADPH oxidase (NOX) are involved in coronary endothelial dysfunction upon various injury factors. Statins inhibited oxidized low‐density lipoprotein‐induced MR clustering and NOX aggregation and activation in these MR clusters in endothelial cells. The present study tested whether the formation of MR‐redox signaling platforms is enhanced in the coronary arterial endothelium in hypercholesterolemic mice and whether statins block such MR‐redox signaling to protect mice from hypercholesterolemia (HC)‐induced injury. Poloxamer 407 (P407) was administrated i.p. (0.5 g/kg) to induce acute HC in mice, which were also intragastricaly fed pravastatin (140 mg/kg/d), simvastatin (70 mg/kg/d), or vehicle for 7 d. P407 caused a 9.8‐fold increase in plasma cholesterol concentration in mice receiving vehicle treatment, while pretreatment of mice with both statins decreased this P407‐induced cholesterol elevation by 64%. In the coronary arterial intima of mice with acute HC, confocal microscopy demonstrated a co‐localization of gp91 phox , p47 phox , acid sphingomyelinase or ceramide within MR clusters. Such co‐localization was rarely observed in arteries of normal mice and significantly reduced by pretreatment of mice with statins. Confocal microscopy of dihydroethidium fluorescence also demonstrated that O 2 •− production in situ was 3 folds higher in the coronary arterial intima of HC mice than that in normal mice, which was inhibited by statins. Taken together, our results indicate that HC enhanced the formation of MR‐redox signaling platforms associated with NOX and that blockade of this MR redox signaling in the coronary endothelium may contribute to the therapeutic effect of statins in preventing endothelial injury and atherosclerosis (supported by NIH grants, HL‐091464, HL57244 and HL‐75316).