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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1473.)
© 2006 American Heart Association, Inc.

Vascular Biology

Comparative Effects of Paclitaxel and Rapamycin on Smooth Muscle Migration and Survival

Role of Akt-Dependent Signaling

Cam Patterson; Sabeen Mapera; Hui-Hua Li; Nageswara Madamanchi; Eleanor Hilliard; Rob Lineberger; Robert Herrmann; Peter Charles

From Carolina Cardiovascular Biology Center and Division of Cardiology (C.P., S.M., H.-H.L, N.M., E.H., R.L., P.C.), University of North Carolina, Chapel Hill, NC; Boston Scientific (R.H.), Natick, Mass.

Correspondence to Cam Patterson, MD, Director, Division of Cardiology and Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126. E-mail cpatters{at}med.unc.edu

Objective— Advances in stent technology have enabled the delivery of drugs to improve outcomes after stent deployment. However, the optimal payloads for stents are not clear, and the appropriate stent-based therapies for high-risk patients, such as diabetics, have not been clearly established.

Methods and Results— We used smooth muscle cell culture models to compare the activities of rapamycin and paclitaxel. Smooth muscle cells were grown in normal or high glucose to induce insulin resistance. Both paclitaxel and rapamycin activate mitogen-activated protein kinase pathways similarly. However, rapamycin potently activates AKT-dependent signaling, an effect that overrides the downregulation of this pathway by insulin resistance and that causes phosphorylation of the AKT-dependent transcription factor FOXO1. This effect is associated with attenuation of the anti-migratory effects of rapamycin under high glucose conditions that are not observed with paclitaxel, as well as with increased protection against ceramide-induced cytotoxicity, both of which are dependent on FOXO1 phosphorylation.

Conclusions— Differences between the ability of rapamycin and paclitaxel to activate AKT may account for their differential cell survival and antichemotactic activities. These observations may provide a basis for understanding clinical differences between rapamycin- and paclitaxel-coated stents. The approaches used in these studies can be expanded to other candidate stent payloads as a method for triage in preclinical studies.

We used smooth muscle cells to compare the activities of rapamycin and paclitaxel. Rapamycin potently activates AKT-dependent signaling, an effect that causes phosphorylation of FOXO1. This effect is associated with attenuation of the anti-migratory effects of rapamycin and with protection against cytotoxicity, both of which are dependent on FOXO1 phosphorylation.

Key Words: migration • signaling • smooth muscle • stent • viability

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