This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 24/2/264    most recent 01.ATV.0000112036.72200.acv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kolmakova, A. Articles by Chatterjee, S. Search for Related Content PubMed PubMed Citation Articles by Kolmakova, A. Articles by Chatterjee, S. Related Collections Lipid and lipoprotein metabolism Other Vascular biology Apoptosis Pathophysiology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:264.)
© 2004 American Heart Association, Inc.

Vascular Biology

Apolipoprotein C-I Induces Apoptosis in Human Aortic Smooth Muscle Cells via Recruiting Neutral Sphingomyelinase

Antonina Kolmakova; Peter Kwiterovich; Donna Virgil; Petar Alaupovic; Carolyn Knight-Gibson; Sergio F. Martin; Subroto Chatterjee

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.

Correspondence to Subroto Chatterjee, 550 North Broadway, Suite 312, Baltimore, MD 21205. 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-) (positive 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 that found 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-

This article has been cited by other articles:

				V. M. Bolanos-Garcia, A. Renault, and S. Beaufils Surface Rheology and Adsorption Kinetics Reveal the Relative Amphiphilicity, Interfacial Activity, and Stability of Human Exchangeable Apolipoproteins Biophys. J., March 1, 2008; 94(5): 1735 - 1745. [Abstract] [Full Text] [PDF]

				M. Westerterp, J. F.P. Berbee, N. M.M. Pires, G. J.D. van Mierlo, R. Kleemann, J. A. Romijn, L. M. Havekes, and P. C.N. Rensen Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E Knockout Mice Circulation, November 6, 2007; 116(19): 2173 - 2181. [Abstract] [Full Text] [PDF]

				P. O. Kwiterovich Jr, S. L. Cockrill, D. G. Virgil, E. S. Garrett, J. Otvos, C. Knight-Gibson, P. Alaupovic, T. Forte, L. Zhang, Z. N. Farwig, et al. A Large High-Density Lipoprotein Enriched in Apolipoprotein C-I: A Novel Biochemical Marker in Infants of Lower Birth Weight and Younger Gestational Age JAMA, April 20, 2005; 293(15): 1891 - 1899. [Abstract] [Full Text] [PDF]