title: Loss of canonical insulin signaling accelerates vascular smooth muscle cell proliferation and migration through changes in p27Kip1 regulation.
abstract: 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.
authors.affiliation: Laboratory of Molecular Cardiology, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA.
authors.forename: Daniel James
authors.initials: DJ
authors.lastname: Lightell
authors.forename: Stephanie Collier
authors.initials: SC
authors.lastname: Moss
authors.forename: Thomas Cooper
authors.initials: TC
authors.lastname: Woods
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D007328:Insulin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus