on December 11, 2003
Published online before print December 11, 2003, doi: 10.1161/01.ATV.0000112036.72200.ac
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Submitted on October 20, 2003
Accepted on December 1, 2003
Apolipoprotein C-I Induces Apoptosis in Human Aortic Smooth Muscle Cells via Recruiting Neutral Sphingomyelinase
Antonina Kolmakova ;
From the Lipid Research Atherosclerosis Division (A.K., P.K., D.V., S.F.M., S.C.) and the Department of Pediatrics (S.C.), Johns Hopkins University, Baltimore, MD; and the Oklahoma Medical Research Foundation (P.A., C.K.-G.), Oklahoma City, OK.
* To whom correspondence should be addressed. E-mail: schatte2{at}jhmi.edu.
Objectives--Apolipoprotein C-I (apoC-I) influences lipoprotein metabolism, but little is known about its cellular effects in aortic smooth muscle cells (ASMC).
Methods and Results--In cultured human ASMC, apoC-I and immunoaffinity purified apoC-I-enriched high-density lipoproteins (HDL) markedly induced apoptosis (5- to 25-fold), compared with control cells, apoC-I-poor HDL, and apolipoprotein C-III (apoC-III) as determined by 4', 6-diamidino-2-phenylindole dihydrochloride staining and DNA ladder assay. Preincubation of cells with GW4869, an inhibitor of neutral sphingomyelinase (N-SMase), blocked apoC-I-induced apoptosis, an effect that was bypassed by C-2 ceramide. The activity of N-SMase was increased 2- to 3-fold in ASMC by apoC-I, apoC-I-enriched HDL, and tumor necrosis factor 
(TNF-) (+ control) after 10 minutes and then decreased over 60 minutes, which is a kinetic pattern not seen with controls, apoC-III, and apoC-I-poor HDL. ApoC-I and apoC-I-enriched HDL stimulated the generation of ceramide, the release of cytochrome c from mitochondria, and activation of caspase-3 greater than it did in controls, apoC-III, and apoC-I-poor HDL. GW4869 inhibited apoC-I-induced production of ceramide and cytochrome c release.
Conclusions--ApoC-I and apoC-I-enriched HDL activate the N-SMase-ceramide signaling pathway, leading to apoptosis in human ASMC, which is an effect that may promote plaque rupture in vivo.
Key words: apolipoprotein C-I • apoptosis • sphingomyelinase • high-density lipoproteins • tumor necrosis factor-
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