DNA hypomethylation and methyltransferase expression in atherosclerotic lesions

• Published in: Vascular medicine (London, England) Vol. 7; no. 1; pp. 5 - 11
• Main Authors: Hiltunen, Mikko O, Turunen, Mikko P, Häkkinen, Tomi P, Rutanen, Juha, Hedman, Marja, Mäkinen, Kimmo, Turunen, Anna-Mari, Aalto-Setalä, Katriina, Ylä-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: Thousand Oaks, CA Sage Publications 01-02-2002; Arnold; Sage Publications Ltd
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Aorta - metabolism; Aorta - pathology; Arteriosclerosis - genetics; Arteriosclerosis - metabolism; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Movement - genetics; Child; Disease Models, Animal; DNA - genetics; DNA - metabolism; DNA Methylation; DNA Modification Methylases - biosynthesis; DNA Modification Methylases - genetics; Female; Gene Expression - genetics; Humans; Male; Medical sciences; Mice; Mice, Knockout; Middle Aged; Models, Cardiovascular; Myocytes, Smooth Muscle - metabolism; Proto-Oncogene Proteins c-sis - biosynthesis; Proto-Oncogene Proteins c-sis - genetics; Rabbits; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tunica Intima - metabolism; atherogenesis; DNA methylation; cell culture; gene expression; Human; Cell culture; Pathophysiology; Enzyme; Pathogenesis; Transferases; Rodentia; Cardiovascular disease; Exploration; Gene expression; Vascular disease; Vertebrata; Mammalia; Gene; Methyltransferases; Mouse; Atherosclerotic plaque; Animal; DNA; Atherosclerosis; Methylation
• ISSN: 1358-836X; 1358-863X; 1477-0377
• DOI: 10.1191/1358863x02vm418oa

Arterial smooth muscle cell (SMC) migration and proliferation are central features in atherogenesis. Altered gene expression and cell proliferation in atherosclerotic lesions have some similar characteristics with certain solid tumors and thus might have similar mechanisms that lead to SMC proliferation. Among cancer cells common features are genome-wide hypomethylation which correlates with transformation and tumor progression, and coincident over-expression of methyltransferase (MTase). The purpose of the present study was to analyze whether alterations in DNA methylation and MTase expression are present in atherosclerotic lesions.
A significant reduction in genomic 5-methylcytosine content was detected in advanced human atherosclerotic lesions and in lesions of ApoE knock-out mice. SMC were shown to develop hypomethylation in vitro during transformation from a contractile to synthetic pheno-type. Balloon denudation of New Zealand White rabbit aorta caused proliferation of intimal SMC with concomitant genomic hypomethylation in the thickened intima. By using in situ hybridization the overall transcriptional activity was found to be increased in clusters of lesion SMC. Marked heterogeneity was seen in MTase mRNA expression in various types of atherosclerotic lesions among intimal and medial SMC.
These findings show that (1) genomic hypomethylation occurs during atherogenesis in human, mouse and rabbit lesions and that it correlates with increased transcriptional activity; (2) MTase is expressed in atherosclerotic lesions; and (3) hypomethylation is present in advanced lesions at the same level as in malignant tumors and may affect cellular proliferation and gene expression in atherosclerotic lesions.