PMID- 21190963
OWN - NLM
STAT- MEDLINE
DCOM- 20110225
LR  - 20211203
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 152
IP  - 2
DP  - 2011 Feb
TI  - Loss of canonical insulin signaling accelerates vascular smooth muscle cell 
      proliferation and migration through changes in p27Kip1 regulation.
PG  - 651-8
LID - 10.1210/en.2010-0722 [doi]
AB  - Insulin resistance is associated with an accelerated rate of atherosclerosis. 
      Vascular smooth muscle cell (VSMC) migration and proliferation are important 
      components of atherosclerosis. To elucidate the effects of the loss of normal 
      insulin receptor (IR) signaling on VSMC function, we compared the proliferation 
      and migration of murine VSMCs lacking the IR (L2-VSMCs) with wild type 
      (WT-VSMCs). We also examined changes in the response of L2-VSMCs to insulin 
      stimulation and to inhibition of the mammalian target of rapamycin (mTOR), a 
      kinase critical in VSMC proliferation and migration. The L2-VSMCs exhibit greater 
      proliferation and migration rates compared with WT-VSMCs. L2-VSMCs also exhibit a 
      resistance to the effects of rapamycin, an mTOR inhibitor, on proliferation, 
      migration, and cell cycle progression. The resistance to mTOR inhibition is 
      coupled with a loss of effect on the cyclin-dependent kinase inhibitor p27(Kip1), 
      an inhibitor of cell cycle progression and VSMC migration. In response to 
      stimulation with physiological insulin, the L2-VSMCs exhibit a loss of Akt 
      phosphorylation and a significantly increased activation of the ERK-1/2 compared 
      with WT-VSMCs. Insulin stimulation also decreased p27(Kip1) mRNA in L2-VSMCs but 
      not in WT-VSMCs. The effect of insulin on p27(Kip1) mRNA was blocked by 
      pretreatment with an ERK-1/2 pathway inhibitor. We conclude that loss of 
      canonical insulin signaling results in increased ERK-1/2 activation in response 
      to physiological insulin that decreases p27(Kip1) mRNA. These data demonstrate a 
      potential mechanism where changes in IR signaling could lead to a decrease in 
      p27(Kip1), accelerating VSMC proliferation and migration.
FAU - Lightell, Daniel James Jr
AU  - Lightell DJ Jr
AD  - Laboratory of Molecular Cardiology, Ochsner Clinic Foundation, New Orleans, 
      Louisiana 70121, USA.
FAU - Moss, Stephanie Collier
AU  - Moss SC
FAU - Woods, Thomas Cooper
AU  - Woods TC
LA  - eng
GR  - P20 RR018766/RR/NCRR NIH HHS/United States
GR  - P20RR018766/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101229
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Insulin)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Movement/*drug effects
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Cyclin-Dependent Kinase Inhibitor p27/*metabolism
MH  - Insulin/*pharmacology
MH  - Mice
MH  - Muscle, Smooth, Vascular/*cytology
MH  - Myocytes, Smooth Muscle/cytology/*drug effects/*metabolism
MH  - Polymerase Chain Reaction
MH  - Receptor, Insulin/genetics/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
PMC - PMC3037159
EDAT- 2010/12/31 06:00
MHDA- 2011/02/26 06:00
PMCR- 2012/02/01
CRDT- 2010/12/31 06:00
PHST- 2010/12/31 06:00 [entrez]
PHST- 2010/12/31 06:00 [pubmed]
PHST- 2011/02/26 06:00 [medline]
PHST- 2012/02/01 00:00 [pmc-release]
AID - en.2010-0722 [pii]
AID - EN-10-0722 [pii]
AID - 10.1210/en.2010-0722 [doi]
PST - ppublish
SO  - Endocrinology. 2011 Feb;152(2):651-8. doi: 10.1210/en.2010-0722. Epub 2010 Dec 
      29.