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The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation
journal contribution
posted on 2013-06-01, 00:00 authored by Smriti Murali Krishna, Anthony Dear, Jeffrey CraigJeffrey Craig, Paul E Norman, Jonathan GolledgePrevious studies have suggested that homocysteine (Hcy) has wide-ranging biological effects, including accelerating atherosclerosis, impairing post injury endothelial repair and function, deregulating lipid metabolism and inducing thrombosis. However, the biochemical basis by which hyperhomocysteinemia (HHcy) contributes to cardiovascular diseases (CVDs) remains largely unknown. Several case-control studies have reported an association between HHcy and the presence of abdominal aortic aneurysms (AAA) and there are supportive data from animal models. Genotypic data concerning the association between variants of genes involved in the methionine cycle and AAA are conflicting probably due to problems such as reverse causality and confounding. The multifactorial nature of AAA suggests the involvement of additional epigenetic factors in disease formation. Elevated Hcy levels have been previously linked to altered DNA methylation levels in various diseases. Folate or vitamin B12 based methods of lowering Hcy have had disappointingly limited effects in reducing CVD events. One possible reason for the limited efficacy of such therapy is that they have failed to reverse epigenetic changes induced by HHcy. It is possible that individuals with HHcy have an "Hcy memory effect" due to epigenetic alterations which continue to promote progression of cardiovascular complications even after Hcy levels are lowered. It is possible that deleterious effect of prior, extended exposure to elevated Hcy concentrations have long-lasting effects on target organs and genes, hence underestimating the benefit of Hcy lowering therapies in CVD patients. Therapies targeting the epigenetic machinery as well as lowering circulating Hcy concentrations may have a more efficacious effect in reducing the incidence of cardiovascular complications.
History
Journal
AtherosclerosisVolume
228Issue
2Pagination
295 - 305Publisher
ElsevierLocation
Amsterdam, The NetherlandseISSN
1879-1484Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2013, Elsevier Ireland Ltd.Usage metrics
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No categories selectedKeywords
AnimalsAortic Aneurysm, AbdominalBiomarkersDNA MethylationEpigenesis, GeneticGenetic Predisposition to DiseaseGenetic TherapyHistonesHomocysteineHumansPhenotypePrognosisRisk FactorsUp-RegulationScience & TechnologyLife Sciences & BiomedicineCardiac & Cardiovascular SystemsPeripheral Vascular DiseaseCardiovascular System & CardiologyAbdominal aortic aneurysmEpigeneticsHcy memory effectPLASMA S-ADENOSYLHOMOCYSTEINESMOOTH-MUSCLE-CELLSLOW-DENSITY-LIPOPROTEINE-DEFICIENT MICENITRIC-OXIDECARDIOVASCULAR-DISEASECORONARY-ARTERYFOLIC-ACIDENDOTHELIAL DYSFUNCTIONVASCULAR-DISEASE
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