Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation
| Autor: | Kim E. Kortekaas, Baohui Xu, Thomas Quertermous, Maximilian Quertermous, Philip S. Tsao, G-One Ahn, Ryuji Toh, Ramendra K. Kundu, Lars Maegdefessel, Soumajit Kundu, Joseph C. Wu, Gary K. Owens, Ronald L. Dalman, Erica Berzin, Ziad A. Ali, Scott C. Roberts, Karen Cheng, Clint L. Miller, Joshua M. Spin, Kelly P. Downing, Azad Raiesdana, Yoko Kojima, Patrícia de Almeida, Henry S. Cheng, Nicholas J. Leeper, D. Ryan Anderson, Eric E. Schadt |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Carotid Artery Diseases
Male Pathology Time Factors Apoptosis Muscle Smooth Vascular Aortic aneurysm Mice Cell Movement Aorta Abdominal Child Cells Cultured Bone Marrow Transplantation Mice Knockout Pancreatic Elastase Proto-Oncogene Proteins c-mdm2 Middle Aged Carotid Arteries Phenotype Child Preschool Knockout mouse RNA Interference Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction Neointima Adult medicine.medical_specialty Tumor suppressor gene Adolescent Genotype Biology Transfection Article Young Adult medicine Animals Humans Benzothiazoles Aged Cell Proliferation Cyclin-Dependent Kinase Inhibitor p15 Vascular disease Cell growth Infant Newborn Infant medicine.disease Mice Inbred C57BL Disease Models Animal Gene Expression Regulation Case-Control Studies Tumor Suppressor Protein p53 Aortic Aneurysm Abdominal Toluene |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 33(1) |
| ISSN: | 1524-4636 |
| Popis: | Objective— Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear. Methods and Results— Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow–derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model. Conclusion— These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|