HOMOCYSTEINE INCREASES CYCLIN-DEPENDENT KINASE IN AORTIC RAT-TISSUE

Background Hyperhomocyst(e)inemia is strongly associated with occlusiv e arterial disease. A direct effect of homocysteine on the proliferati on of smooth muscle cells was proposed recently. This observation led us to examine the effect of homocysteine on cyclin-dependent kinase, t he starter of mitosis and reflecting proliferation. Methods and Result s Seventy Him:OFA rats were divided into seven groups. For 12 weeks, 1 0 rats were fed homocysteine 25 mg/kg body weight per day, 10 were fed 50 mg/kg body wt per day, and 10 were fed 100 mg/kg body weight per d ay; 10 were given homocysteic acid 100 mg/kg body weight per day, 10 w ere administered cysteine 100 mg/kg body weight per day, and 10 were g iven ascorbic acid 270 mg/kg body weight per day. Ten remained untreat ed and served as controls. Aortic cyclin-dependent kinase was determin ed at the transcriptional (mRNA) and protein levels. Phosphokinase C a nd aortic homocyst(e)ine also were evaluated in aortic tissue. Aortic cyclin-dependent kinase protein was significantly (P=.0001) elevated i n the three homocysteine-treated groups, and mRNA cyclin-dependent kin ase levels were significantly elevated in the rats given the 50 and 10 0 mg/kg body weight per day protocol. Endothelial damage was shown at higher homocysteine doses as reflected by circulating ACE and von Will ebrand factor changes. Proliferation of cells of the aortic wall by br omodeoxyuridine incorporation could be shown in the high-dose homocyst eine group only. Conclusions Our findings indicate that homocysteine s pecifically stimulates aortic cyclin-dependent kinase at the transcrip tional level, with the possible consequence of proliferation of aortic cells as revealed by incorporation of bromodeoxyuridine in the aortic wall.