© 1999 American Heart Association, Inc.
Original Contribution |
Activation of p38 Mitogen-Activated Protein Kinase by Oxidized LDL in Vascular Smooth Muscle Cells
Mediation via Pertussis Toxin–Sensitive G Proteins and Association With Oxidized LDL-Induced Cytotoxicity
From the Shanghai Institute of Cell Biology (Q.J., S.-M.X., Z.-J.C., W.-B.Z., R.Z., G.P.), Chinese Academy of Sciences, Shanghai; Department of Cardiology (Q.J., Y.-W.Q.), Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
Correspondence to Gang Pei, PhD, Shanghai Institute of Cell Biology, Chinese Academy of Sciences, 320 Yue Yang Rd, Shanghai 200031, People's Republic of China. E-mail gangpei{at}sunm.shcnc.ac.cn
Abstract—Oxidized low-density lipoproteins (oxLDL) have been shown to play a crucial role in atherosclerosis, but the underlying molecular mechanisms have not been fully understood. The present study showed that oxLDL strongly evoked phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) in rat vascular smooth muscle cells (VSMCs) in concentration- and time-dependent manners, reaching the maximal activation at 100 µg/mL within 5 minutes. The results from immunofluorescence staining also revealed that p38 MAPK was activated by oxLDL in 5 minutes, and the activated 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 scavenger receptors and was not affected by tyrosine kinase inhibitors. However, activation of p38 MAPK was effectively blocked by pretreatment with pertussis toxin and was significantly reduced by phospholipase C inhibitor U-73122. OxLDL also inhibited forskolin-stimulated cAMP 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 the culture medium, reduced [3H]thymidine incorporation, and attenuated mitochondrial 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 effectively activated p38 MAPK in VSMCs, which was likely mediated via pertussis toxin–sensitive G proteins, and the p38 activation was functionally associated with oxLDL-induced cytotoxicity in VSMCs.
Key Words: atherosclerosis • oxidized LDL • p38 mitogen-activated protein kinase • vascular smooth muscle • cytotoxicity
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