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Abstract

The cyclin-dependent kinase inhibitors are key regulators of cell cycle progression. Although implicated in carcinogenesis, they inhibit the proliferation of a variety of normal cell types, and their role in diverse human diseases is not fully understood. Here, we report that p27Kip1 plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow–derived (BM-derived) immune cells that migrate into vascular lesions. Lesion formation after mechanical arterial injury was markedly increased in mice with homozygous deletion of p27Kip1, characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion was substantially increased when BM-derived cells from p27–/– mice repopulated vascular lesions induced by mechanical injury in p27+/+ recipients, in contrast to p27+/+ BM donors. To determine the contribution of immune cells to vascular injury, transplantation was performed with BM derived from RAG–/– and RAG+/+ mice. RAG+/+ BM markedly exacerbated vascular proliferative lesions compared with what was found in RAG–/– donors. Taken together, these findings suggest that vascular repair and regeneration is regulated by the proliferation of BM-derived hematopoietic and nonhematopoietic cells through a p27Kip1-dependent mechanism and that immune cells largely mediate these effects.

Authors

Manfred Boehm ... Xuan Qu, Elizabeth G. Nabel

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Total citations by year

Year: 2014 2012 2008 2006 2005 2004 Total
Citations: 1 1 1 4 1 1 9
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Citations to this article (9)

Title and authors Publication Year
TGF-  Signaling Mediates Endothelial-to-Mesenchymal Transition (EndMT) During Vein Graft Remodeling
BC Cooley, J Nevado, J Mellad, D Yang, CS Hilaire, A Negro, F Fang, G Chen, H San, AD Walts, RL Schwartzbeck, B Taylor, JD Lanzer, A Wragg, A Elagha, LE Beltran, C Berry, R Feil, R Virmani, E Ladich, JC Kovacic, M Boehm
Science Translational Medicine 2014
Magnolol attenuates neointima formation by inducing cell cycle arrest via inhibition of ERK1/2 and NF-κB activation in vascular smooth muscle cells
R Karki, OM Ho, DW Kim
Biochimica et Biophysica Acta (BBA) - General Subjects 2012
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HV Huikuri, K Kervinen, M Niemela, K Ylitalo, M Saily, P Koistinen, ER Savolainen, H Ukkonen, M Pietila, JK Airaksinen, J Knuuti, TH Makikallio
European Heart Journal 2008
Cytostatic gene therapy for occlusive vascular disease
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Expert Opinion on Therapeutic Patents 2006
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K Sarkar, SK Sharma, R Sachdeva, F Romeo, L Garza, JL Mehta
Expert Review of Cardiovascular Therapy 2006
Atheroma development in apolipoprotein E-null mice is not regulated by phosphorylation of p27Kip1 on threonine 187
SM Sanz-González, RM de Mera, NP Malek, V Andrés
Journal of Cellular Biochemistry 2006
Enzyme Inhibitors Series
M Boehm, M Crook
Enzyme Inhibitors Series 2006
p27kip1 Deficiency Confers Susceptibility to Gastric Carcinogenesis in Helicobacter pylori–Infected Mice
N Kuzushita, AB Rogers, NA Monti, MT Whary, MJ Park, BI Aswad, H Shirin, A Koff, H Eguchi, SF Moss
Gastroenterology 2005
Rationale and study design of the CardioGene Study: genomics of in-stent restenosis
SK Ganesh, KA Skelding, L Mehta, K O’Neill, J Joo, G Zheng, J Goldstein, R Simari, E Billings, NL Geller, D Holmes, WW O’Neill, EG Nabel
Pharmacogenomics 2004

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