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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:485.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Critical Role of Lipid Raft Redox Signaling Platforms in Endostatin-Induced Coronary Endothelial Dysfunction

Si Jin; Yang Zhang; Fan Yi; Pin-Lan Li

From the Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University.

Correspondence to Pin-Lan Li, MD, PhD, Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, 410 N 12th, Richmond, VA 23298. E-mail pli{at}vcu.edu

Objective— Endostatin (EST) was found to initiate a redox signaling cascade associated with activation of NADPH oxidase in endothelial cells (ECs). The present study tested whether EST stimulates clustering of ceramide-enriched lipid rafts (LRs), which assembles and activates NADPH oxidase to form redox signaling platforms.

Methods and Results— Using confocal microscopy, we first demonstrated a colocalization of LR clusters with NADPH oxidase subunits, gp91^phox and p47^phox in the ECs membrane on EST stimulation. Immunoblot analysis of floated detergent-resistant membrane fractions found that in LR fractions NADPH oxidase subunits gp91^phox and p47^phox are enriched and that the activity of this enzyme increased dramatically, as measured by electron spin resonance (ESR) spectrometry. This EST-increased LR platform formation was shown to be attenuated by inhibition or RNA interference of acid sphingomyelinase (A-SMase). Functionally, EST pretreatment significantly impaired bradykinin or A23187-induced vasodilation in isolated small coronary arteries, which could be partially reversed by LR disruptors.

Conclusions— The early injury effect of EST on the vascular endothelium is associated with the formation of redox signaling platforms via lipid raft clustering.

Besides its proapototic effects, EST is also able to induce endothelial dysfunction. This early-stage action of EST is associated with LR clustering and consequent assembling and activation of NADPH oxidase.

Key Words: endostatin • NADPH oxidase • coronary • endothelium • sphingolipid

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