Regulation of cell cycle entry by PTEN in smooth muscle cell proliferation of human coronary artery bypass conduits

Guanghong Jia, Amit K. Mitra, Deepak M. Gangahar, Devendra K. Agrawal

Research output: Contribution to journalArticle

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Abstract

Proliferation of smooth muscle cells (SMCs) is the key event in the pathogenesis of intimal hyperplasia (IH) leading to coronary artery bypass graft (CABG) occlusion. The saphenous vein (SV) conduits are often affected by IH, while the internal mammary artery (IMA) conduits remain remarkably patent. SMC proliferation is mediated by the cell cycle, under the control of cyclin-dependent kinases (cdks), cdk-inhibitors and the retinoblastoma protein (Rb). Early passage of the SMCs through the cell cycle involves crossing the non-reversible G1 checkpoint, the restriction (R) point. In this study, we investigated the effect of mitogenic insulin-like growth factor (IGF)-1 stimulation on the R-point and its relationship with the phosphorylation of Rb protein and the cdk inhibitors p21 and p27 in SV and IMA SMCs. We observed no change in the R-point following IGF-1 activation in either SV or IMA SMCs. However, Rb-phosphorylation occurred much earlier and was quantitatively greater in SV SMCs than IMA. Overexpression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in SV SMCs followed by IGF-1 activation significantly decreased the expression of cyclin E and pRb and induced p27 expression in SV SMCs, while, pRb levels were markedly decreased and p27 levels were significantly increased in IMA SMCs. Silencing the PTEN gene by siRNA transfection of IMA SMCs significantly induced the expression of pRb and inhibited p27 expression, while, the expression levels of cyclin E, pRb, p21 and p27 were unaffected by the silencing of PTEN in SV SMCs. These results demonstrate that the PTEN plays a critical role in regulating cell cycle entry. Therefore, overexpression of PTEN possibly by means of gene therapy could be a viable option in regulating the cell cycle in SV SMCs in the treatment of vein graft disease.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2009

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All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Molecular Medicine

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