title: Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Sealy Center for Molecular Cardiology, the Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston, 77555-0553, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ruef
authors.forename: G N
authors.initials: GN
authors.lastname: Rao
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Bode
authors.forename: C
authors.initials: C
authors.lastname: Patterson
authors.forename: A
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: M S
authors.initials: MS
authors.lastname: Runge
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C027576:4-hydroxy-2-nonenal