on January 20, 2003
Published online before print January 20, 2003, doi: 10.1161/01.CIR.0000048191.75585.60
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Submitted on August 23, 2002
From the Departments of Pediatrics (G.A.V., F.L., H.Z., J.L., K.K.) and Medicine (A.A.), College of Medicine, University of Florida, Gainesville. * To whom correspondence should be addressed. E-mail: visnega{at}peds.ufl.edu.
Background--Rapamycin is an immunosuppressive agent with antiproliferative properties against not only lymphocytes but also vascular endothelial and smooth muscle cells, and it reduces the fibroproliferative response to vascular injury. Heme oxygenase-1 (HO-1) has also been shown to have graft protective effects and to inhibit vascular remodeling. In this study, we evaluated whether there is an interaction between rapamycin and HO-1. Methods and Results--In human pulmonary artery endothelial or smooth muscle cells, HO-1 expression was evaluated in response to rapamycin or wortmannin, an inhibitor of the upstream modulator of mammalian target of rapamycin (mTOR) PI-3K. We also evaluated whether the inhibitory actions of rapamycin on platelet-derived growth factor-dependent proliferation was mediated by HO using the chemical inhibitor tin protoporphyrin. Rapamycin induced HO-1 expression in both pulmonary endothelial and smooth muscle cells, whereas no to little increase was seen in response to another immunosuppressive agent, cyclosporin A. HO-1 expression was also increased in response to wortmannin, suggesting that the PI-3K-mTOR pathway is required for this induction. Inhibition of HO activity resulted in a loss of the antiproliferative activity of rapamycin in growth factor-stimulated smooth muscle cells. Conclusions--The induction of HO-1 expression by rapamycin and, more importantly, the effects of tin protoporphyrin, an inhibitor of HO activity, on the antiproliferative actions of rapamycin suggest that the effects of rapamycin may be, at least in part, modulated by its actions on HO-1.
Revised on October 30, 2002
Accepted on October 30, 2002
Rapamycin Induces Heme Oxygenase-1 in Human Pulmonary Vascular Cells. Implications in the Antiproliferative Response to Rapamycin
Gary A. Visner DO*,
Key words: heme oxygenase • sirolimus • wortmannin • cells, endothelial • cells, muscle, smooth
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