Induction of cyclin a gene expression by homocysteine in vascular smooth muscle cells

Homocysteine is an important and independent risk factor for arteriosclerosis, We showed previously that homocysteine stimulates vascular smooth muscle cell proliferation, a hallmark of arteriosclerosis. We show here that homocysteine and serum increased DNA synthesis synergistically in both human and rat aortic smooth muscle cells (RASMCs), Treatment of quiescent RASMCs with 1 mM homocysteine or 2% calf serum for 36 h increased cyclin A mRNA levels by 8- and 14-fold, respectively, whereas homocysteine plus serum increased cyclin A mRNA levels by 40-fold, indicating a synergistic induction of cyclin A mRNA. Homocysteine did not increase the half-life of cyclin A mRNA (2.9 h), but it did increase the transcriptional rate of the cyclin A gene in nuclear run-on experiments, The positive effect of homocysteine on cyclin A gene transcription was confirmed by our finding that homocysteine increased cyclin A promoter activity and ATF-binding protein levels in RASMCs, Finally, I mM homocysteine increased cyclin A protein levels and cyclin A-associated kinase activity by threefold, This homocysteine-induced expression of cyclin A may accelerate progression of arteriosclerotic lesions by promoting proliferation of vascular smooth muscle cells.