Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis.
Cyclin kinase inhibitor p21 is one of the most potent inhibitors of aortic smooth muscle cell proliferation, a key mediator of atherosclerosis. This study tests if p2l deficiency will result in severe atherosclerosis in a mouse model. p21-/- and strain matched wild type mice were fed with high fat diet for 21 weeks. Analysis for biochemical parameters (cholesterol, triglycerides) in serum and mRNA expression of CD36, HO-1, TGF-beta, IFN-gamma, TNF-alpha, PPAR-gamma and NADPH oxidase components (p22phox, NOX-1 and Rac-1) was performed in aortic tissues by Real Time PCR. p21-/- mice gained significantly (p < 0.01) more weight than wild type mice, triglycerides (p < 0.05) and cholesterol levels (p < 0.01) were more pronounced in the sera of p21-/- compared to wild type mice fed with high fat diet. High fat diet resulted in significantly decreased TGF-beta (p < 0.02), HO-l (p < 0.02) and increased CD36 (p < 0.03) mRNA expression in aortic tissues of p21-/- mice compared to animal fed with regular diet. IFN-gamma mRNA expression (235 +/- 11 folds) increased significantly in high fat diet fed p21-/- mice and a multifold modulation of PPAR-gamma(136 +/- 7), p22phox, NOX-1 and Rac-1 (15-35-folds) mRNA in aortic tissues from p21-/- mice compared to the wild type mice. Severity of atherosclerotic lesions was significantly higher in p21-/- compared to wild type mice. The results demonstrate that the deficiency of p21 leads to altered expression of pro-atherogenic genes, and severe atherosclerosis in mice fed with high fat diet. This opens the possibility of p21 protein as a therapeutic tool to control progression of atherosclerosis.
Khanna
Ashwani K
AK
Department of Medicine (Cardiology), University of Maryland, Baltimore, USA. akhanna@medicine.umaryland.edu
D000821:Animal Feed; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics*; D018955:CD36 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D018955:CD36 Antigens; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019255:NADPH Oxidases