Submitted to: Free Radicals in Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2006
Publication Date: 9/1/2006
Citation: Nie, L., Wise, M.L., Peterson, D.B., Meydani, M. 2006. Mechanism by which avenanthramide-c, a polyphenol of oats, blocks cell cycle progression in vascular smooth muscle cells. Free Radicals in Biology and Medicine. 41(5):702-8. Interpretive Summary: There is an increasing awareness of the potential health benefits derived from eating certain food groups. Epidemiological data have shown that consumption of oats, for example, is associated with lowering of blood cholesterol levels and reduction of cardiovascular disease. Oat uniquely contains a group of polyphenol compounds termed avenanthramides. We previously demonstrated avenanthramide-C dose-dependently inhibits vascular smooth muscle cell proliferation. Proliferation of vascular smooth muscle cells is one of the hallmarks of atherosclerosis. In this study we demonstrate that treatment of a vascular smooth muscle cell line with avenanthramide-C resulted in the arrest of the cell cycle in the G1 phase. This growth inhibitory effect of avenanthramide-C appeared to be mediated through a molecular signaling cascade which ultimately inhibits the phosphorylation of retinoblastoma protein (pRb), a prerequisite for cellular progression into the S1 phase and hence cell proliferation. These results portend the value of oats in combating cardiovascular disease over and above the already known benefit of cholesterol reduction.
Technical Abstract: Previously, we reported that avenanthramides (Avns), polyphenols of oats, inhibited the serum-induced proliferation of vascular smooth muscle cells (SMC), which is an important process in the development of atherosclerosis. In the present study, we investigated the mechanism by which Avn-c, one of the major forms of Avn in oats, inhibits proliferation of SMC. Rat embryonic aortic smooth muscle cell line A10 was used in this study. Flow cytometry analysis revealed that treatment of A10 cells with 80 microM Avn-c arrested the cell cycle in G1 phase as indicated by an increase in the number of the cells in G1 phase and a decrease in the number of cells in S phase. This cell cycle arrest was associated with a decrease in the phosphorylation of retinoblastoma protein (pRb); its hyperphosphorylation is a hallmark of the G1 to S transition in the cell cycle. The inhibition of pRb phosphorylation with Avn-c was accompanied by a decrease in cyclin D1 expression and an increase in cyclin-dependent kinase inhibitor p21cip1 expression, without significant changes in p27kip1 expression. Furthermore, Avn-c treatment increased the expression level and stability of p53 protein, which could account for the increase of p21cip1 expression. Our results demonstrate for the first time that Avn-c, which is a unique polyphenol found in oats, inhibits SMC proliferation at G1 phase by up-regulating p53-p21cip1 pathway and inhibiting pRB phosphorylation. This inhibitory effect of Avn-c on SMC proliferation is another indication of the potential health benefit of oat consumption in the prevention of cardiovascular disease.