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Regulation of vascular smooth muscle proliferation by heparin: inhibition of cyclin-dependent kinase 2 activity by p27(kip1).

ABSTRACT: Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed the effect of heparin on cell cycle in VSMC. Our results indicate that the heparin-induced block in G(1) to S phase transition is imposed by p27(kip1)-mediated inhibition of cyclin-dependent kinase 2 activity. Further analysis of p27(kip1) mRNA levels showed that the increase in p27(kip1) protein levels in heparin-treated VSMC occurs at posttranscriptional levels. We present evidence that heparin causes stabilization of p27(kip1) protein during G(1) phase and thereby prevents activation of cyclin-dependent kinase 2.

SUBMITTER: Fasciano S

PROVIDER: S-EPMC3972062 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Regulation of vascular smooth muscle proliferation by heparin: inhibition of cyclin-dependent kinase 2 activity by p27(kip1).

Fasciano Stephen S Patel Rekha C RC Handy Indhira I Patel Chandrashekhar V CV

The Journal of biological chemistry 20050224 16

Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed t ...[more]

PMID: 15731113

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Project description:Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (? 2 ?m by 0.5 ?m), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.

Dataset Information

Regulation of vascular smooth muscle proliferation by heparin: inhibition of cyclin-dependent kinase 2 activity by p27(kip1).

Publications

Regulation of vascular smooth muscle proliferation by heparin: inhibition of cyclin-dependent kinase 2 activity by p27(kip1).

Similar Datasets

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