From the Division of Cardiology and Sealy Center for Molecular
Cardiology, the Department of Human Biological Chemistry and Genetics,
University of Texas Medical Branch at Galveston; and the Division of
Cardiology (C.B.), University of Heidelberg (Germany).
Correspondence to Marschall S. Runge, MD, PhD, University of Texas Medical Branch, Division of Cardiology, 5.106 John Sealy Hospital, 301 University Blvd, Galveston, TX 77555-0553. E-mail mrunge{at}utmb.edu
Background—Atherosclerotic lesion
formation is a complex process, in part mediated by inflammatory and
oxidative mechanisms including lipid peroxidation. To further
characterize the potential role of lipid peroxidation products in
atherogenesis, we studied the effects of 4-hydroxy-2-nonenal (HNE) on
rat aortic smooth muscle cell growth.
Methods and Results—HNE, at concentrations of 1.0 and 2.5
µmol/L, significantly stimulated rat aortic smooth muscle cell growth
as determined by cell counts, [3H]-thymidine uptake, and
incorporation of bromo-deoxyuridine. To characterize the mechanism of
HNE-induced mitogenesis, its effect on activation of intracellular
growth signaling pathways was examined. Treatment with HNE resulted in
activation of extracellular signal-regulated protein kinases ERK1 and
ERK2, induction of c-fos and c-jun
protein expression, and an increase in transcription factor AP-1 DNA
binding activity. In addition, HNE induced expression of
platelet-derived growth factor-AA (PDGF-AA) protein, and an
anti–PDGF-AA antibody specifically inhibited HNE-mediated DNA
synthesis, suggesting that growth factor induction may play a role in
HNE-induced vascular smooth muscle cell growth. The role of
redox-sensitive mechanisms in this process was further supported by the
observation that HNE-induced DNA synthesis and AP-1 activation were
inhibited by the antioxidants N-acetylcysteine and
pyrrolidine dithiocarbamate.
Conclusions—These data demonstrate that HNE, one of several
important lipid peroxidation products, induces rat aortic smooth
muscle cell growth through redox-sensitive mechanisms and growth factor
expression. These observations are consistent with a role for
lipid peroxidation products in vascular smooth muscle cell growth
in atherogenesis.
© 1998 American Heart Association, Inc.
Basic Science Reports
Induction of Rat Aortic Smooth Muscle Cell Growth by the Lipid Peroxidation Product 4-Hydroxy-2-Nonenal
Key Words: atherosclerosis • oxidation • lipids • signal transduction • mitogens
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