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-mediated apoptosis in vascular smooth muscle cells requires p73
1 Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA
2 Immunology Graduate Group, and Cancer Center, University of California, Davis, Davis, CA, USA
3 Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
4 Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA; Immunology Graduate Group, and Cancer Center, University of California, Davis, Davis, CA, USA; Department of Veterans Affairs, Northern California Health Care System, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: rhweiss{at}ucdavis.edu.
Atherosclerosis, now considered an inflammatory process, is the leading cause of death in the western world and is manifested by variety of diseases in multiple organ systems. Due to its prevalence and associated morbidity, novel therapies directed at arresting this progressive process are urgently needed. The inflammatory mediator TNF
, 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 pro-apoptotic protein in vascular smooth muscle cells, which are involved in plaque progression as well as rupture, we asked whether TNF mediates apoptosis in these cells through p73. We now show that p73 is present in spindle-shaped cells within human atheroma, and p73
, 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 when added to these cells in the presence of serum-containing media increases p73 expression and causes apoptosis in both rat and human vascular smooth muscle cells. Inhibition of p73 activity using a dominant inhibitory N-terminally deleted p73 plasmid results in markedly decreased TNF-induced apoptosis. Thus, p73 is likely a mediator of the apoptotic effect of TNF in the vasculature, such that future targeting of the p73 isoforms may ultimately prove useful in novel atherosclerosis therapies.
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