PMID- 19020099
OWN - NLM
STAT- MEDLINE
DCOM- 20090105
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 105
IP  - 48
DP  - 2008 Dec 2
TI  - Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors.
PG  - 19006-11
LID - 10.1073/pnas.0809743105 [doi]
AB  - Despite the use of the sirolimus (rapamycin) drug-eluting coronary stent, 
      diabetics are at increased risk of developing in-stent restenosis for unclear 
      reasons. Hyperleptinemia, which often coexists with diabetes and metabolic 
      syndrome, is an independent risk factor for progression of coronary artery 
      disease. It has not been determined whether elevated circulating leptin decreases 
      the efficacy of the sirolimus drug-eluting stent in inhibiting neointimal 
      hyperplasia, the process underlying restenosis after stenting. Here we show that 
      leptin activates the mammalian target of rapamycin (mTOR) signaling pathway in 
      primary murine vascular smooth muscle cells (VSMC) and stimulates VSMC 
      proliferation in a PI3K-dependent fashion. Exogenous leptin, administered at 
      levels comparable to those found in obese humans, promotes neointimal VSMC 
      hyperplasia in a murine femoral artery wire injury model. Leptin significantly 
      increases the dose of the mTOR inhibitor sirolimus that is required for effective 
      inhibition of neointimal formation. Combination therapy with LY294002, a PI3K 
      inhibitor, and sirolimus effectively inhibits leptin-enhanced neointimal 
      hyperplasia. These data show that, in the setting of hyperleptinemia, higher 
      doses of an mTOR inhibitor, or combination therapy with mTOR and PI3K inhibitors, 
      inhibits neointimal hyperplasia after arterial injury. These studies may explain 
      the higher rates of restenosis observed in diabetics treated with a 
      sirolimus-eluting coronary stent and suggest a potential novel therapeutic 
      approach for inhibiting in-stent restenosis in such patients.
FAU - Shan, Jian
AU  - Shan J
AD  - Department of Physiology, College of Physicians and Surgeons of Columbia 
      University, New York, NY 10032, USA.
FAU - Nguyen, Thomas B
AU  - Nguyen TB
FAU - Totary-Jain, Hana
AU  - Totary-Jain H
FAU - Dansky, Hayes
AU  - Dansky H
FAU - Marx, Steven O
AU  - Marx SO
FAU - Marks, Andrew R
AU  - Marks AR
LA  - eng
GR  - K99 HL109133/HL/NHLBI NIH HHS/United States
GR  - HL007854/HL/NHLBI NIH HHS/United States
GR  - F32HL088815/HL/NHLBI NIH HHS/United States
GR  - T32 HL007854/HL/NHLBI NIH HHS/United States
GR  - F32 HL088815/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20081119
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Leptin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Receptors, Leptin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Cells, Cultured
MH  - Female
MH  - Humans
MH  - Hyperplasia/metabolism/*pathology
MH  - Leptin/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Muscle, Smooth, Vascular/cytology/drug effects
MH  - Myocytes, Smooth Muscle/cytology/drug effects/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinases/*metabolism
MH  - Receptors, Leptin/genetics/metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/pharmacology
MH  - Stents
MH  - TOR Serine-Threonine Kinases
MH  - Tunica Intima/*drug effects/metabolism/*pathology
PMC - PMC2585045
COIS- The authors declare no conflict of interest.
EDAT- 2008/11/21 09:00
MHDA- 2009/01/06 09:00
PMCR- 2008/11/19
CRDT- 2008/11/21 09:00
PHST- 2008/11/21 09:00 [pubmed]
PHST- 2009/01/06 09:00 [medline]
PHST- 2008/11/21 09:00 [entrez]
PHST- 2008/11/19 00:00 [pmc-release]
AID - 0809743105 [pii]
AID - 5624 [pii]
AID - 10.1073/pnas.0809743105 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):19006-11. doi: 
      10.1073/pnas.0809743105. Epub 2008 Nov 19.