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Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus
Tulane Heart and Vascular Institute and the Department of Physiology, School of Medicine, Tulane University, 1430 Tulane Avenue, SL-48, New Orleans, LA 70112, USA
Department of Pharmacology & Experimental Therapeutics, LSU Health Sciences Center—New Orleans, New Orleans, LA 70112, USA
Received: 14 January 2013; in revised form: 1 May 2013 / Accepted: 8 May 2013 / Published: 27 May 2013
Abstract: The proliferation and migration of vascular smooth muscle cells (VSMCs) in the intima of an artery, known as intimal hyperplasia, is an important component of cardiovascular diseases. This is seen most clearly in the case of in-stent restenosis, where drug eluting stents are used to deliver agents that prevent VSMC proliferation and migration. One class of agents that are highly effective in the prevention of in-stent restenosis is the mammalian Target of Rapamycin (mTOR) inhibitors. Inhibition of mTOR blocks protein synthesis, cell cycle progression, and cell migration. Key to the effects on cell cycle progression and cell migration is the inhibition of mTOR-mediated degradation of p27Kip1 protein. p27Kip1 is a cyclin dependent kinase inhibitor that is elevated in quiescent VSMCs and inhibits the G1 to S phase transition and cell migration. Under normal conditions, vascular injury promotes degradation of p27Kip1 protein in an mTOR dependent manner. Recent reports from our lab suggest that in the presence of diabetes mellitus, elevation of extracellular signal response kinase activity may promote decreased p27Kip1 mRNA and produce a relative resistance to mTOR inhibition. Here we review these findings and their relevance to designing treatments for cardiovascular disease in the presence of diabetes mellitus.
Keywords: intimal hyperplasia; p27Kip1; mammalian Target of Rapamycin; diabetes mellitus; vascular smooth muscle cells
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Woods, T.C. Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus. Pharmaceuticals 2013, 6, 716-727.
Woods TC. Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus. Pharmaceuticals. 2013; 6(6):716-727.
Woods, Thomas C. 2013. "Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus." Pharmaceuticals 6, no. 6: 716-727.