Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system

Objective: Methylation of the promoter region of the estrogen receptor gene alpha (ER alpha) occurs as a function of age in human colon, and results i n inactivation of gene transcription. In this study, we sought to determine whether such age-related methylation occurs in the cardiovascular system, and whether it is associated with atherosclerotic disease. Methods: We used Southern blot analysis to determine the methylation state of the ER alpha gene in human light atrium, aorta, internal mammary artery, saphenous vein, coronary atherectomy samples, as well as cultured aortic endothelial cells and smooth muscle cells. Results: An age related increase in ER alpha gene methylation occurs in the right atrium (range 6 to 19%, R = 0.36, P<0.05). Significant levels of ER alpha methylation were detected in both veins and arteries. In addition, ER alpha gene methylation appears to be increased i n coronary atherosclerotic plaques when compared to normal proximal aorta ( 10+/-2% versus 4+/-1%, P<0.01). In endothelial cells er;planted from human aorta and grown in vitro, ER alpha gene methylation remains low. In contras t, cultured aortic smooth muscle cells contain a high level of ER alpha gen e methylation (19-99%). Conclusions: Methylation associated inactivation of the ER alpha gene in vascular tissue may play a role in atherogenesis and aging of the vascular system. This potentially reversible defect may provid e a new target for intervention in heart disease. (C) 1999 Elsevier Science B.V. All rights reserved.