Abstract 914: Cyclin Kinase Inhibitor p21: An Attractive Therapeutic Tool To Limit Development Of Atherosclerosis: Indirect Evidence With p21−/− Mouse Model Of Atherosclerosis.
HYPTHESIS: Aberrant proliferation of vascular smooth muscle cells and neointimal lymphocytes are the key events in the pathogenesis of atherosclerosis. The precise mechanism of aberrant proliferation and ensuing inflammation remains unknown. Cyclin kinase inhibitor p21 has been shown to restrain the proliferation of lymphocytes and aortic smooth muscle cells. In this study, the role of p21 in the pathogenesis of atherosclerosis is explored, with a hypothesis that p2l−/− mice will develop more severe atherosclerosis than wild type controls, fed with high fat diet.
METHODS: p21−/− and strain matched wild type mice were fed with high fat diet for 6 weeks. Mice were sacrificed and analysis for biochemical parameters (cholesterol, triglycerides), mRNA expression of CD36, HO-1, TGF-beta, IFN-gamma, TNF-alpha, PPAR-gamma and NADPH oxidase components (p22phox, NOX-1,Rac-1) was performed in aortic tissues by RT-PCR and Real Time PCR. Quantitative hispathological analysis was also performed.
RESULTS: The results demonstrate that p21−/− mice gained significantly (p<0.01) more weight than wild type mice. The increase of triglycerides (p<0.05) and cholesterol levels (p,0.01) was more pronounced in sera of p21−/− mice compared to wild type fed with high fat diet. High fat diet resulted in a significant decreased TGF-beta (p<0.02), increased CD36 (p<0.03), and decreased HO-l mRNA (p<0.02) expression in aortic tissues of p21−/− mice compared to wild type mice. A significantly increased IFN-gamma mRNA expression (60 ± 3 folds) was observed in high fat diet fed p21−/− mice and a multifold (15–35-folds) modulation of PPAR-gamma, p22phox, NOX-1 and RAC-1 mRNA was observed in aortic tissues from p21−/− mice compared to the wild type mice. Severity of atherosclerotic lesions was significantly higher in p21−/− mice compared to the wild type mice.
CONCLUSIONS: These results demonstrate that the deficiency of p21 leads to inflammation and the development of atherosclerosis. Therefore, controlling of the cell cycle is critical for the treatment of atherosclerosis in the presence of hypercholesterolemia. Therefore, based on its effect on inflammation, recombinant p21 protein may provide an attractive therapeutic avenue for the treatment of atherosclerosis.