Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 May 27;6(6):716-27.
doi: 10.3390/ph6060716.

Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus

Thomas Cooper Woods  1
Affiliations

Dysregulation of the Mammalian Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes Mellitus

Thomas Cooper Woods. Pharmaceuticals (Basel). .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Under quiescent conditions, p27Kip1 levels are high inhibiting cdk2 and RhoA activity thereby blocking VSMC proliferation and migration (Left Panel). In normal VSMCs, mitogenic stimulation promotes the proteasome dependent degradation of p27Kip1 protein through, at least in part, activation of the mTOR pathway (Center Panel). Loss of p27Kip1 permits increased activation of cdk2 and RhoA leading to VSMC proliferation and migration. In the presence of diabetes, ERK activity is increased, which in turn destabilizes p27Kip1 mRNA (Right Panel). This lowers p27Kip1 protein levels before mitogenic stimulation occurs, allowing for greater proliferation and migration. Activation of the mTOR pathway functions as it did under normal conditions and will promote down regulation of p27Kip1 protein as before.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ross R. The pathogenesis of atherosclerosis—An update. N. Engl. J. Med. 1986;314:488–500. doi: 10.1056/NEJM198602203140806. - DOI - PubMed
    1. Ross R., Glomset J.A. The pathogenesis of atherosclerosis (second of two parts) N. Engl. J. Med. 1976;295:420–425. doi: 10.1056/NEJM197608192950805. - DOI - PubMed
    1. Ross R., Glomset J.A. The pathogenesis of atherosclerosis (first of two parts) N. Engl. J. Med. 1976;295:369–377. doi: 10.1056/NEJM197608122950707. - DOI - PubMed
    1. Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature. 1993;362:801–809. doi: 10.1038/362801a0. - DOI - PubMed
    1. Ross R. Atherosclerosis—An inflammatory disease. N. Engl. J. Med. 1999;340:115–126. - PubMed

LinkOut - more resources