Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients

Abstract

BackgroundCirculating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients.MethodsPeripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing.ResultsDDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase.ConclusionHypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.

Epigenetic Reprogramming in Atherosclerosis

“…Moreover, homocysteine is able to impair EPC adhesion function through DDAH2 promoter hypermethylation, since the effect is reverted by pretreatment with Aza, an inhibitor of DNA methyltransferase. These results also corroborate a role of epigenetic methylation in the progression of atherosclerosis [63].…”

146 Demethylation Treatment Restores Erectile Function in a Rat Model of Hyperhomocysteinemia

“…46 Niu et al concluded in a clinical study that hypermethylation of DDAH-2 promoter contributed to the impaired function of endothelial progenitor cells in coronary artery disease patients. 29 Jia et al found hcy induced apoptosis of endothelial cells via elevating the methylation level of DDAH-2 promoter regions in cultured human umbilical vein endothelial cells. 53 Similar results were further confirmed in some other studies in vivo.…”

Physical activity and progenitor cell-mediated endothelial repair in chronic heart failure: Is there a role for epigenetics?

“…Recently, a rat genome-wide epigenetic and proteomic study assessing the impairment of the angiogenic properties of EPCs in response to a high-salt diet (Karcher et al, 2015) has found Notch4 hypermethylation, as confirmed by decreased protein levels; this suggests that methylation status is a potential mechanism of angiogenic competency alteration in EPCs. Niu et al (2014) investigated whether hypermethylation of dimethylarginine dimethylaminohydrolase 2 (DDAH2) promoter contributes to impair EPC function in patients with coronary artery disease (CAD). DDAH2 predominates in eNOS expressing tissues, and impaired DDAH2 activity and/or expression appears to be responsible for elevation of plasma asymmetric dimethylarginine in atherosclerosis and CVDs.…”