PMID- 23532775
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130328
LR  - 20211021
IS  - 1524-5012 (Print)
IS  - 1524-5012 (Linking)
VI  - 13
IP  - 1
DP  - 2013 Spring
TI  - Relative resistance to Mammalian target of rapamycin inhibition in vascular 
      smooth muscle cells of diabetic donors.
PG  - 56-60
AB  - BACKGROUND: Diabetes mellitus is associated with an increased risk of 
      cardiovascular disease. Intimal thickening, a component of cardiovascular 
      disease, entails the proliferation and migration of vascular smooth muscle cells 
      (VSMCs). Inhibition of the mammalian target of rapamycin (mTOR) blocks VSMC 
      proliferation, in part through an increase in the cyclin-dependent kinase 
      inhibitor, p27(Kip1). The use of mTOR inhibitors, such as rapamycin, is effective 
      clinically in inhibiting intimal thickening. This efficacy is reduced in diabetic 
      subjects, however, suggesting a change in the role of the mTOR pathway in intimal 
      thickening under diabetic conditions. METHODS: To examine whether diabetes 
      induced changes in the role of mTOR in VSMC proliferation, we compared the 
      response to rapamycin of human coronary artery VSMCs from diabetic (DM-huCASMC 
      [human coronary artery smooth muscle cell]) and nondiabetic (ND-huCASMC) 
      subjects. RESULTS: The DM-huCASMCs exhibited a relative resistance to rapamycin's 
      inhibition of proliferation. Activation of the mTOR effector p70(S6kinase) was 
      inhibited in rapamycin-treated DM-huCASMCs as in ND-huCASMCs. While ND-huCASMCs 
      exhibited the normal increase in p27(Kip1) in response to rapamycin treatment, 
      the DM-huCASMCs did not. Additionally, activation of the extracellular signal 
      response kinase pathway was increased in the DM-huCASMCs, suggesting a potential 
      pathway mediating the mTOR-independent decrease in p27(Kip1). CONCLUSION: We 
      conclude that diabetes is accompanied by a relative resistance to the effects of 
      mTOR inhibition on VSMC proliferation through a loss of mTOR's effects on 
      p27(Kip1) levels. These data provide insight into the effects of insulin 
      resistance on the role of mTOR in regulating intimal thickening.
FAU - Lightell, Daniel J Jr
AU  - Lightell DJ Jr
AD  - Institute for Translational Research, Molecular Cardiology Laboratory, Ochsner 
      Clinic Foundation, New Orleans, LA.
FAU - Woods, T Cooper
AU  - Woods TC
LA  - eng
GR  - P20 RR018766/RR/NCRR NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Ochsner J
JT  - Ochsner journal
JID - 101125795
PMC - PMC3603189
OTO - NOTNLM
OT  - Coronary artery disease
OT  - TOR serine-threonine kinases
OT  - cyclin-dependent kinase inhibitor p27
OT  - vascular smooth muscle
COIS- Funding: This work was supported by Award Number P20RR018766 from the National 
      Center for Research Resources of the National Institutes of Health.
EDAT- 2013/03/28 06:00
MHDA- 2013/03/28 06:01
PMCR- 2013/03/01
CRDT- 2013/03/28 06:00
PHST- 2013/03/28 06:00 [entrez]
PHST- 2013/03/28 06:00 [pubmed]
PHST- 2013/03/28 06:01 [medline]
PHST- 2013/03/01 00:00 [pmc-release]
AID - TOJ-12-0069 [pii]
PST - ppublish
SO  - Ochsner J. 2013 Spring;13(1):56-60.