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Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens

  • Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.

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Metadaten
Document Type:Article
Language:English
Author:Martin Lange, Tatsuya Fujikawa, Anna Koulova, Sona Kang, Michael J. Griffin, Antonio D. Lassaletta, Anna Erat, Edda Tobiasch, Cesario Bianchi, Nassrene Elmadhun, Frank W. Sellke, Anny Usheva
Parent Title (English):Cell Cycle
Volume:13
Issue:2
First Page:315
Last Page:323
ISSN:1538-4101
DOI:https://doi.org/10.4161/cc.27056
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24240190
Publisher:Taylor & Francis
Date of first publication:2013/11/12
Note:
This work was supported, in whole or in part, by National Institute of Health Grants R01HL062458 (to AU), R01HL46716, R01HL69024 (to FWS.), Training grant 5T32-HL076134 (to AL), American Heart Association Grant-in-Aid Program 11GRNT5250000 (to CB), and from the Thoracic Surgery Foundation for Research and Education Fellowship (to AL).
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2015/04/02