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

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 mu mol/L, significantly stimulated rat aortic smooth muscle cell growth as determined by cell counts, [H-3]-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-I 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.