[Qing Jing, et al. Circ Res, 1999, 84(7):831]
Oxidized low-density lipoproteins (oxLDL) have been shown to play a crucial role in atherosclerosis, but the underlyingmolecular mechanisms have not been fully understood. The present study showed that oxLDLstrongly evoked phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) in rat vascular smooth muscle cells (VSMCs) in concentration-and time-dependentmanners, reaching the maximal activation at 100 μg/ml within 5 minutes. The results from immunofluorescencestaining also revealed that p38 MAPK was activated by oxLDL in 5 minutes, and theactivated p38 MAPK was translocated from cytoplasm to nucleus of VSMCs in 15 minutes.Activation of p38 MAPK by oxLDL was apparently not mediated by their classical scavengerreceptors and was not affected by tyrosine kinase inhibitors. However, activation of p38MAPK was effectively blocked by pretreatment with pertussis toxin and was significantlyreduced by phospholipase C inhibitor U-73122. OxLDL also inhibited forskolin-stimulatedcAMP accumulation and increased inositol phosphate formation. More interestingly,inhibition of p38 MAPK by its specific inhibitor SB203580 significantly blocked oxLDL-induced cytotoxicity (increased leakage of cytoplasmic lactate dehydrogenase to theculture medium, reduced ³ H thymidine incorporation, and attenuatedmitochondrial metabolism of tetrazolium salt,(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), MTS) in VSMCs, and pretreatment with pertussis toxin also inhibited oxLDL-induced cytotoxicity. Taken together, our data clearly demonstrated that oxLDL effectivelyactivated p38 MAPK in VSMCs, which was likely mediated via pertussis toxin-sensitive Gproteins, and the p38 activation was functionally associated with oxLDL-inducedcytotoxicity in VSMCs.