Inhibition of oxidized low-density lipoprotein-induced apoptosis in endothelial cells by nitric oxide - Peroxyl radical scavenging as an antiapoptotic mechanism

Proatherogenic oxidized low-density lipoprotein (oxLDL) induces endothelial apoptosis, We investigated the anti-apoptotic effects of intracellular and extracellular nitric oxide ((NO)- N-.) donors, iron chelators, cell-permeable superoxide dismutase (SOD), glutathione peroxidase mimetics, and nitrone spin traps. Peroxynitrite (ONOO-)-modified oxLDL induced endothelial apoptosis was measured by DNA fragmentation, TUNEL assay, and caspase-3 activation. Results indicated the following: (i) the lipid fraction of oxLDL was primarily responsible for endothelial apoptosis, (ii) Endothelial apoptosis was potently inhibited by (NO)-N-. donors and lipophilic phenolic antioxidants, OxLDL severely depleted Bcl-2 levels in endothelial cells and (NO)-N-. donors restored Bcl-2 protein in oxLDL-treated cells. (iii) The pretreatment of a lipid fraction derived from oxLDL with sodium borohydride or potassium iodide completely abrogated apoptosis in endothelial cells, suggesting that lipid hydroperoxides induce apoptosis, (iv) Metalloporphyrins dramatically inhibited oxLDL-induced apoptosis in endothelial cells. Neither S-nitrosation of caspase-3 nor induction of Hsp70 appeared to play a significant role in the antiapoptotic mechanism of (NO)-N-. in oxLDL- induced endothelial apoptosis, We propose that cellular lipid peroxyl radicals or lipid hydroperoxides induce an apoptotic signaling cascade in endothelial cells exposed to oxLDL, and that (NO)-N-. inhibits apoptosis by scavenging cellular lipid peroxyl radicals.

See More