Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal

• Published in: Circulation (New York, N.Y.) N.Y.), 1998-03, Vol.97 (11), p.1071-1078
• Main Authors: RUEF, J, RAO, G. N, FENGZHI LI, BODE, C, PATTERSON, C, BHATNAGAR, A, RUNGE, M. S
• Format: Article
• Language: English
• Subjects: Aldehydes - pharmacology; Animals; Aorta - cytology; Aorta - drug effects; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Calcium-Calmodulin-Dependent Protein Kinases - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiology. Vascular system; Cell Division - drug effects; Cells, Cultured; Cysteine Proteinase Inhibitors - pharmacology; Lipid Peroxidation; Male; Medical sciences; Mitosis - drug effects; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.97.11.1071

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. HNE, at concentrations of 1.0 and 2.5 micromol/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. 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.