Epigenetic Modulation of Atherosclerosis: Recent Findings

Updated:Jun 13,2014
AHA Science News

Atherosclerosis is the underlying cause of the majority of clinical cardiovascular events. The fundamental role of epigenetics in the development of atherosclerosis has become increasingly recognized. The following studies investigate novel mechanisms by which epigenetic modifications influence disease progression.


NOS1 Methylation and Carotid Artery Intima-Media Thickness in Children
Breton CV, Park C, Siegmund K, Gauderman WJ, Whitfield-Maxwell L, Hodis HN, Avol E, Gilliland FD. NOS1 Methylation and Carotid Artery Intima-Media Thickness in Children. Circ Cardiovasc Genet. 2014; 7: 116-122.
 

   

Nitric oxide (NO) is thought to play a cardioprotective role by regulating vascular tone and blood pressure, as well as inhibiting platelet aggregation and smooth muscle cell (SMC) proliferation. NO is produced by NO synthase (NOS) enzymes, which include the isoform NOS1. This study observed an association between percentage DNA methylation of the NOS1 gene and carotid artery intima-media thickness (CIMT) among 377 participants in the Children's Health Study.


Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell Plasticity
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell Plasticity. Circulation. 2013; 128: 2047-2057.
 

 

Endothelial dysfunction has been associated with atherosclerotic cardiovascular disease (CVD). A key event in this process involves the aggregation of leukocytes on the vessel wall, which is mediated by the transcriptional upregulation of adhesion molecules (CAM) in endothelial cells. This study provides evidence that Brahma related gene 1 (Brg1) and Brahma (Brm), components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, link inflammation-induced endothelial injury and the pathogenesis of atherosclerosis by coordinating epigenetic modifications necessary for CAM transactivation.


Proinflammatory Stimuli Engage Brahma Related Gene 1 and Brahma in Endothelial Injury
Fang F, Chen D, Yu L, Dai X, Yang Y, Tian W, Cheng X, Xu H, Weng X, Fang M, Zhou J, Gao Y, Chen Q, Xu Y. Proinflammatory Stimuli Engage Brahma Related Gene 1 and Brahma in Endothelial Injury. Circ Res. 2013; 113: 986-996.
 

 

Increases in sympathovagal disbalance, atrial fibrillation, and postapneic blood pressure have been linked to obstructive sleep apnea. In resistant hypertensive patients, renal denervation has been shown to reduce renal efferent as well as afferent sympathetic activity and blood pressure. Renal deprivation and atenolol were shown to modulate vagally-mediated negative tracheal pressure–induced atrial effective refractory period shortening, highlighting the importance of autonomic disbalance in obstructive sleep apnea–associated atrial fibrillation.


Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol
Kumar A, Kumar S, Vikram A, Hoffman TA, Naqvi A, Lewarchik CM, Kim YR, Irani K. Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol. Arterioscler Thromb Vasc Biol. 2013; 33: 1936-1942.
 

 

Low-density lipoprotein (LDL) cholesterol promotes endothelial dysfunction and plays a key role in the development of atherosclerotic plaque. Endothelial Kruppel-like Factor 2 (KLF2) is a transcription factor that regulates vascular homeostasis. This study found that endothelial KLF2 expression is repressed by LDL through DNA and histone methylation, identifying a new mechanism by which LDL cholesterol may affect the risk of atherosclerotic CVD.


SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes
Zawada, AM, Rogacev KS, Hummel B, Grün OS, Friedrich A, Rotter B, Winter P, Geisel J, Fliser D, Heine GH. SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes. Circ Cardiovasc Genet. 2012; 5: 611-620.
 

 

Patients with chronic kidney disease (CKD) are at increased risk for CVD, but few studies have investigated the epigenetics of CKD-associated CVD. In this study, the authors performed genome-wide analyses of DNA methylation in stable patients undergoing hemodialysis therapy and in healthy controls. In their analysis of epigenetic modifications associated with CKD, they identify candidate genes linked with inflammatory and proatherogenic processes.


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