title: Hyperhomocysteinemia, DNA methylation and vascular disease.
abstract: Hyperhomocysteinemia (HHcy) has been established as a potent independent risk factor for cardiovascular disease (CVD) and the underlying mechanism is largely unknown. We were the first to propose that hypomethylation is the key biochemical mechanism by which homocysteine (Hcy) inhibits endothelial cell (EC) growth. We reported that clinically relevant concentrations of Hcy (10-50 micromol/L) exerts highly selective inhibitory effects on cyclin A transcription and EC growth through a hypomethylation related mechanism, which blocks cell cycle progression and endothelium regeneration. Recently, we demonstrated that Hcy reduces DNA methyltransferase 1 (DNMT1) activity and demethylates cyclin A promoter leading to cyclin A chromatin remodeling. We found that adenovirus-transduced DNMT1 gene expression reverses the inhibitory effect of Hcy on cyclin A expression and EC growth inhibition. We hypothesize that DNA hypomethylation is a key biochemical mechanism responsible for Hcy-induced cyclin A suppression and growth inhibition in EC and contributes to CVD.
authors: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Md S
authors: MS
authors: Jamaluddin
authors: Xiaofeng
authors: X
authors: Yang
authors: Hong
authors: H
authors: Wang
mesh_terms: D002843:Chromatin / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014652:Vascular Diseases / Q000150:complications* / Q000235:genetics
chemical_list: D002843:Chromatin; D019925:Cyclin A