Caspase-3-dependent apoptosis in vascular smooth muscle cell by proteasome inhibition.
The effects of a number of substances on neointima formation following angioplasty have been investigated in animal models. It was suggested that delivering of proteasome inhibitor to the site of vascular injury would be a potential therapeutic approach in prevention of vascular restenosis. But the mechanisms underlying biologic activities of proteasome inhibition in vascular smooth muscle cells (VSMCs) are largely unknown. We have investigated effects of proteasome inhibition on VSMCs using proteasome inhibitor MG115. MG115 induced apoptotic death in VSMCs as determined by viability, morphology, and DNA fragmentation. Proteasome inhibition was accompanied by up-regulation of p53, p21, and p27. In contrast, there were no appreciable alterations in the levels of Bcl-2 and Bax. Proteasome inhibition was followed by activation of caspase-3 but not of -8. The induction of apoptosis was suppressed by treatment with a selective inhibitor of the caspase-3 family, z-DEVD-fmk but not by NG-monomethyl-L-arginine. These results indicate that proteasome inhibition induces apoptosis in VSMCs by activation of caspase-3.
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000517:prevention & control; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D007976:Leupeptins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008840:Microfilament Proteins / Q000502:physiology; D009124:Muscle Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000503:physiopathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D016277:Ventricular Function, Left
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007976:Leupeptins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009842:Oligopeptides; C058992:Tagln protein, mouse; D016159:Tumor Suppressor Protein p53; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases