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DNA hypomethylation and methyltransferase expression in atherosclerotic lesions
Mikko O Hiltunen1, Mikko P Turunen, Tomi P Häkkinen
1AI Virtanen Institute, University of Kuopio, Finland.
Abstract:
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 overexpression 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 phenotype. 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.
Insights
Atherosclerosis involves changes in DNA methylation, similar to cancer. This study found genome-wide hypomethylation in arterial smooth muscle cells during lesion development, suggesting a shared mechanism with tumor progression.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Atherosclerosis Research
Background:
- Smooth muscle cell (SMC) migration and proliferation are key in atherogenesis.
- Altered gene expression in atherosclerotic lesions resembles that in solid tumors, suggesting shared mechanisms.
- Cancer cells exhibit genome-wide hypomethylation and methyltransferase (MTase) overexpression, linked to transformation and progression.
Purpose of the Study:
- To investigate DNA methylation alterations and MTase expression in atherosclerotic lesions.
- To determine if epigenetic changes in atherosclerosis mirror those in cancer.
Main Methods:
- Analysis of genomic 5-methylcytosine content in human and mouse atherosclerotic lesions.
- In vitro studies of SMC transformation and hypomethylation.
- In vivo studies using balloon denudation in rabbits.
- In situ hybridization to assess transcriptional activity and MTase mRNA expression.
Main Results:
- Significant reduction in genomic 5-methylcytosine content in advanced human and ApoE knock-out mouse lesions.
- SMC showed in vitro hypomethylation during phenotype transformation.
- Balloon denudation induced SMC proliferation and genomic hypomethylation in rabbit aorta intima.
- Increased transcriptional activity and heterogeneous MTase mRNA expression observed in lesion SMC.
Conclusions:
- Genomic hypomethylation occurs during atherogenesis across species and correlates with increased transcriptional activity.
- Methyltransferase (MTase) is expressed in atherosclerotic lesions.
- Hypomethylation levels in advanced lesions resemble those in malignant tumors, potentially impacting SMC proliferation and gene expression.