Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients

Abstract

DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease.

Association between DNA methylation and coronary heart disease or other atherosclerotic events: A systematic review

“…In total, 51 articles met our eligibility criteria (Supplementary Table 1) and were included in the analysis. Of the 51 selected studies, 17 included participants from Europe [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] 14 from China [23][24][25][26][27][28][29][30][31][32][33][34][35][36], six from USA [37][38][39][40][41][42], three from India [43][44][45], two from Canada [46,47], and one each from Japan [48], Malaysia [49], Iran [50], Russia [51], Brazil [52] and Mexico [53]…”

The impact of high‐intensity interval training on ventricular remodeling in patients with a recent acute myocardial infarction—A randomized training intervention pilot study

“…Details on the inclusion and exclusion criteria have been previously described elsewhere. 17,18 Importantly, AMI (ST elevation myocardial infarction or non-ST elevation myocardial infarction) was based on the universal definition. 19 For more detailed information on the exclusion criteria see section S1 of the Supporting Information.…”

Preliminary study of the relationship between promoter methylation of the ANGPTL2 gene and coronary heart disease

“…ANGPTL2 expression is regulated by DNA methylation. Nguyen et al have shown that DNA hypomethylation in the promoter region of ANGPTL2 was associated with post‐ACS differently from that of age‐matched healthy controls . Nevertheless, to the best of our knowledge, no experiments have been conducted to demonstrate the correlation between the promoter methylation of the ANGPTL2 gene and the risk of CHD in a Han Chinese population.…”

“…Nguyen et al have shown that DNA hypomethylation in the promoter region of ANGPTL2 was associated with post-ACS differently from that of age-matched healthy controls. 17 Nevertheless, to the best of our knowledge, no experiments have been conducted to demonstrate the correlation between the promoter methylation of the ANGPTL2 gene and the risk of CHD in a Han Chinese population. The aim of the present study was to assess whether aberrant promoter methylation of the ANGPTL2 gene was associated with the risk of CHD in Han Chinese on the coast of China and to explore the interaction between methylation levels and clinical characteristics.…”

“…Abundant expression of ANGPTL2 was detected in adipose tissue and other organs, including skeletal muscle, heart, endothelial cells, lung, and kidney . Early reports state that post‐ACS patients in the cardiovascular prevention center of the Montreal Heart Institute had elevated circulating levels of ANGPTL2 . ANGPTL2 expression is regulated by DNA methylation.…”