TNF-alpha-mediated apoptosis in vascular smooth muscle cells requires p73.
Atherosclerosis, now considered an inflammatory process, is the leading cause of death in the Western world and is manifested by a variety of diseases in multiple organ systems. Because of its prevalence and associated morbidity, novel therapies directed at arresting this progressive process are urgently needed. The inflammatory mediator TNF-alpha, which is known to contribute to apoptosis in vascular smooth muscle cells, has been shown to be intimately involved in the atherosclerotic process, being present at elevated levels in human atheroma as well as possibly being responsible for plaque rupture, a clinically devastating event. In light of our earlier finding that p73 is a proapoptotic protein in vascular smooth muscle cells, which are involved in plaque progression as well as rupture, we asked whether TNF-alpha mediates apoptosis in these cells through p73. We now show that p73 is present in spindle-shaped cells within human atheroma, and p73beta, an isoform that is pivotal in both apoptosis and growth suppression, is induced in vascular smooth muscle cells in vitro by serum but not by PDGF-BB. In addition, TNF-alpha, when added to these cells in the presence of serum-containing media, increases p73beta expression and causes apoptosis in both rat and human vascular smooth muscle cells. Inhibition of p73 activity with a dominant inhibitory NH2-terminally deleted p73 plasmid results in markedly decreased TNF-alpha-induced apoptosis. Thus p73beta is likely a mediator of the apoptotic effect of TNF-alpha in the vasculature, such that future targeting of the p73 isoforms may ultimately prove useful in novel atherosclerosis therapies.
Tang
Vincent
V
Division of Nephrology, GBSF, Rm. 6312, Department of Internal Medicine, University of California, One Shields Ave., Davis, California 95616, USA.
Dhirapong
Amy
A
Yabes
Annoel P
AP
Weiss
Robert H
RH
D000818:Animals; D001013:Aorta, Thoracic; D017209:Apoptosis; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D001769:Blood; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D014409:Tumor Necrosis Factor-alpha; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins