title: Alternation of histone and DNA methylation in human atherosclerotic carotid plaques.
abstract: Little is known about epigenetics and its possible role in atherosclerosis. We here analysed histone and DNA methylation and the expression of corresponding methyltransferases in early and advanced human atherosclerotic carotid lesions in comparison to healthy carotid arteries. Western Blotting was performed on carotid plaques from our biobank with early (n=60) or advanced (n=60) stages of atherosclerosis and healthy carotid arteries (n=12) to analyse di-methylation patterns of histone H3 at positions K4, K9 and K27. In atherosclerotic lesions, di-methylation of H3K4 was unaltered and that of H3K9 and H3K27 significantly decreased compared to control arteries. Immunohistochemistry revealed an increased appearance of di-methylated H3K4 in smooth muscle cells (SMCs), a decreased expression of di-methylated H3K9 in SMCs and inflammatory cells, and reduced di-methylated H3K27 in inflammatory cells in advanced versus early atherosclerosis. Expression of corresponding histone methyltransferases MLL2 and G9a was increased in advanced versus early atherosclerosis. Genomic DNA hypomethylation, as determined by PCR for methylated LINE1 and SAT-alpha, was observed in early and advanced plaques compared to control arteries and in cell-free serum of patients with high-grade carotid stenosis compared to healthy volunteers. In contrast, no differences in DNA methylation were observed in blood cells. Expression of DNA-methyltransferase DNMT1 was reduced in atherosclerotic plaques versus controls, DNMT3A was undetectable, and DNMT3B not altered. DNA-demethylase TET1 was increased in atherosclerosisc plaques. The extent of histone and DNA methylation and expression of some corresponding methyltransferases are significantly altered in atherosclerosis, suggesting a possible contribution of epigenetics in disease development.
authors.forename: A
authors.initials: A
authors.lastname: Greißel
authors.forename: M
authors.initials: M
authors.lastname: Culmes
authors.forename: R
authors.initials: R
authors.lastname: Napieralski
authors.forename: E
authors.initials: E
authors.lastname: Wagner
authors.forename: H
authors.initials: H
authors.lastname: Gebhard
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.forename: A
authors.initials: A
authors.lastname: Zimmermann
authors.forename: H-H
authors.initials: HH
authors.lastname: Eckstein
authors.affiliation: Alma Zernecke, MD, Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Ismaninger Str. 22, D-81675 Munich, Germany, Phone: 0049-89-4140-5168, Fax: 0049-89-4140-4861, E-mail: alma.zernecke@uni-wuerzburg.de.
authors.forename: A
authors.initials: A
authors.lastname: Zernecke
authors.affiliation: Jaroslav Pelisek, PhD, Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Ismaninger Str. 22, D-81675 Munich, Germany, Phone: 0049-89-4140-5168, Fax: 0049-89-4140-4861, E-mail: J.Pelisek@lrz.tum.de.
authors.forename: J
authors.initials: J
authors.lastname: Pelisek
mesh_terms: D000368:Aged; D001773:Blood Cells / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004790:Enzyme Induction; D005260:Female; D006649:Histocompatibility Antigens / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D020084:Long Interspersed Nucleotide Elements; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; D006649:Histocompatibility Antigens; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
keywords: Carotid artery; DNA and histone methylation; atherosclerosis; epigenetics; methyltransferases