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Rapamycin antagonizes NF-B nuclear translocation activated by TNF- in primary vascular smooth muscle cells and enhances apoptosis

¹Invasive Cardiology Unit, Clinica Pineta Grande, Castelvolturno; and ²Department of Biochemistry and Medical Biotechnology, University of Naples "Federico II," Naples, Italy

Submitted 17 July 2005 ; accepted in final form 14 January 2006

Several lines of evidence support the view that rapamycin inhibits NF-B. TNF-, a potent inducer of NF-B, is released after artery injury (e.g., balloon angioplasty) and plays an important role in inflammation and restenosis. We investigated the effect of rapamycin on NF-B activation and apoptosis in vascular smooth muscle cells (VSMCs) stimulated with TNF-. Using EMSA, we found that TNF- caused NF-B nuclear translocation in VSMCs after 1 h of incubation. Rapamycin inhibited IB degradation, thereby preventing nuclear translocation. Activation of NF-B was accompanied by an increase of Bcl-xL and Bfl-1/A1 proteins, detected by Western blot assay, whereas rapamycin prevented the TNF--induced enhancement of these antiapoptotic proteins. The extent of apoptosis of VSMCs exposed to TNF- was significantly enhanced by rapamycin. The effect of rapamycin appeared to be independent of the phosphatidylinositol 3-kinase/Akt-protein kinase B survival pathway, because the phosphatidylinositol 3-kinase inhibitor wortmannin neither prevented IB degradation nor increased apoptosis of cells incubated with TNF-. Finally, we demonstrate that the large immunophilin FK-506 binding protein FKBP51 is essential for TNF--induced NF-B activation in VSMCs. Our findings show that rapamycin inhibits NF-B activation and acts in concert with TNF- in induction of VSMC apoptosis.

inflammation; restenosis; vascular injury

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