DNA hypomethylation and methyltransferase expression in atherosclerotic lesions

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 prolifera...

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Veröffentlicht in:Vascular medicine (London, England) England), 2002-02, Vol.7 (1), p.5-11
Hauptverfasser: Hiltunen, Mikko O, Turunen, Mikko P, Häkkinen, Tomi P, Rutanen, Juha, Hedman, Marja, Mäkinen, Kimmo, Turunen, Anna-Mari, Aalto-Setalä, Katriina, Ylä-Herttuala, Seppo
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container_title Vascular medicine (London, England)
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creator Hiltunen, Mikko O
Turunen, Mikko P
Häkkinen, Tomi P
Rutanen, Juha
Hedman, Marja
Mäkinen, Kimmo
Turunen, Anna-Mari
Aalto-Setalä, Katriina
Ylä-Herttuala, Seppo
description 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.
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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.</abstract><cop>Thousand Oaks, CA</cop><pub>Sage Publications</pub><pmid>12083735</pmid><doi>10.1191/1358863x02vm418oa</doi><tpages>7</tpages></addata></record>
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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
title DNA hypomethylation and methyltransferase expression in atherosclerotic lesions
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