Arachidonic acid-derived oxidation products initiate apoptosis in vascular smooth muscle cells.
The mechanism of arachidonic acid (AA)-induced apoptosis in vascular smooth muscle cells (VSMCs) was studied in the A-10 rat aortic smooth muscle cell line. Treatment of serum-deprived VSMCs with 50 microM AA for 24 h resulted in a loss of cell viability. The apoptotic effect of AA was characterized by annexin V binding, sub-G1 population of cells, cell shrinkage and chromatin condensation. AA-induced VSMC death was attenuated by antioxidants alpha-tocopherol and glutathione, the hydrogen peroxide (H2O2) scavenger catalase and by serum proteins, albumin and gamma globulins. Moreover, the AA peroxidation products, 12(S)-hydroperoxyeicosatetraenoic acid (HPETE), 15(S)-HPETE, 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) caused VSMC apoptosis. These data suggest an oxidative mechanism of AA-induced VSMC death. The apoptotic effect of AA was pH-dependent, being inhibited by extracellular alkalinization to pH 8.0. AA inhibited serum-stimulated cell cycle progression in quiescent cells, but not in proliferating cells. In conclusion, AA, through its oxidation products causes VSMC apoptosis. Antioxidants, by inhibiting VSMC apoptosis, may prevent consequent pathological events such as atherosclerotic plaque rupture.
Kalyankrishna
Shailaja
S
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis 38163, USA.
Parmentier
Jean-Hugues
JH
Malik
Kafait U
KU
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000196:embryology; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004247:DNA / Q000096:biosynthesis; D015289:Leukotrienes / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology; D008315:Malondialdehyde / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D051381:Rats
D000447:Aldehydes; D000975:Antioxidants; D016895:Culture Media, Serum-Free; D015289:Leukotrienes; D008054:Lipid Peroxides; D016718:Arachidonic Acid; D008315:Malondialdehyde; C021201:12-HPETE; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D004247:DNA; C027576:4-hydroxy-2-nonenal