Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling.
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.


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.
Patterson
Cam
C
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, USA. cpatters@med.unc.edu
Mapera
Sabeen
S
Li
Hui-Hua
HH
Madamanchi
Nageswara
N
Hilliard
Eleanor
E
Lineberger
Rob
R
Herrmann
Robert
R
Charles
Peter
P
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*
D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D020123:Sirolimus