Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis

Atherosclerosis is one of the major causes of death in the modern world. Despite large efforts, its pathogenesis remains largely unclear. More recently, atherosclerosis is considered to be a disease of inflammation [1-4]. The precise events leading to inflammation/immune activation in atherosclerosis are not fully understood. Aberrant proliferation of smooth muscle cells is one of the key factors in the pathogenesis of atherosclerosis. Therefore, molecules that control cellular proliferation play a significant role in the understanding of underlying mechanisms of the pathogenesis of atherosclerosis. Transforming growth factor-beta (TGF-β) is one of the most potent inhibitor of smooth muscle cell proliferation [5], its expression decreases in atherosclerosis [6,7], highlighting its role in the pathogenesis of atherosclerosis [8]. Besides, these reported protective effects of TGF-β, its role in atherosclerosis is controversial because studies have demonstrated a causative role of TGF-β in the pathogenesis of atherosclerosis is reported based on the studies, which demonstrate that active TGF-β in smooth muscle cells promote lipid accumulation via increased synthesis [9-11] and deposition of proteoglycan in intima, known to be associated with increased atherosclerosis [12,13]. In another study, TGF-β expression was considered to be a determinant for the extent to which developing atherosclerotic lesions are stabilized by a collagen-rich fibrous cap and higher levels of TGF-β in SMC of stable lesions compared to the unstable lesions were observed [14]. These studies suggest that the role of TGF-β may be detrimental in atherosclerosis. Studies have shown that TGF-β induces expression of cyclin kinase inhibitor p21, which mediates its inhibitory effects [15]. Overexpression of p21 has been shown to reverse atherosclerosis in experimental models of atherosclerosis. [16]. In addition to inducing expression of protective molecules like p21, TGF-β also inhibits the expression