Elevated methylation of cyclin dependent kinase inhibitor 2B contributes to the risk of coronary heart disease in women

Abstract

Cyclin dependent kinase inhibitor 2B (CDKN2B) encodes a cyclin-dependent kinase inhibitor that may enhance the formation of atherosclerotic plaques. The aim of the present study was to investigate the contribution of CDKN2B promoter methylation on the risk of coronary heart disease (CHD). The present results indicated a significant association between increased CDKN2B methylation and the risk of CHD (adjusted P=0.043). A breakdown analysis according to sex demonstrated that CDKN2B methylation was significantly associated with the risk of CHD in women (adjusted P=0.010), but not in men. A further breakdown analysis by age indicated a significant association of CHD in the women >60 years (P=0.024). Luciferase reporter gene assay results indicated that the CDKN2B promoter fragment significantly enhanced luciferase activity (P<0.001). In addition, CDKN2B transcription was significantly enhanced following treatment with 5-aza-2′-deoxycytidine methylation inhibitor in human aortic endothelial cells (HAEC) and human primary coronary artery smooth muscle cells (HPCASMC; P<0.05 and P<0.01), but not in 293 cells. Notably, estrogen treatment reduced CDKN2B methylation of several CpGs and significantly increased CDKN2B gene expression levels in HAEC, HPCASMC and 293 cells (P<0.05 and P<0.01). Additionally, treatment of HAEC and HPCASMC with simvastatin and γ-carboxy-L-glutamic acid reduced CDKN2B promoter methylation and increased CDKN2B transcription concomitantly. The present study suggests that CDKN2B promoter methylation may be associated with sex dimorphism in the pathogenesis of CHD.

Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside

“…Specifically, an increasing interest in circulating epigenetic molecules is providing novel findings that may aid physicians in a more accurate risk stratification [ 99 ]. DNA methylation is a pivotal contributor to a balanced immune response toward the graft, due to regulation by both the innate and adaptive immune systems, with primarily T cells as the key players of alloreactivity and targets for immunosuppressive drugs [ 27 , 28 ]. Interestingly, FOXP3 gene expression was significantly higher in biopsy samples of rejectors collected before rejection in comparison with non-rejectors, and showed the tendency to predict rejection events [ 20 ].…”

“…At the molecular level, trimetazidine can switch the metabolic cellular state from beta-oxidation toward glucose oxidation by inhibiting synthesis or carnitine-facilitated transport of fatty acids so that cardiomyocytes can obtain more energy [ 131 ]. Recently, it has been reported that trimetazidine may exert its cardio-protective role in women by affecting the DNA methylation profile of the cyclin dependent kinase inhibitor 2b (CDKN2B) gene [ 27 , 28 ]. Trimetazidine is being studied in a randomized controlled trial (NCT03273387) which aims to determine if 3 months of treatment (35 mg twice a day) combined with standard therapy can alter right ventricle function in PAH patients.…”

Sexually dimorphic DNA-methylation in cardiometabolic health: A systematic review

“…Eight articles [48][49][50][51][52][53][54][55] investigated the associations between DNAm and CHD and MI. All studies applied a candidate-gene approach and included a total of 2,353 participants 1,010 women and 1,343 men from China, Italy and the Netherlands.…”

Research development in tumor therapy: role of iron-related nanoparticles

“…Amongst more than a dozen trace elements essential to the human body, iron ranks first both in value and in quantity. Cells have established various sophisticated mechanisms to control their iron homeostasis strictly, including ferritin (Ft) [5], transferrin (TF) [6], and various iron-regulating proteins [7][8][9].…”

“…Given the influence of iron, it is particularly necessary to regulate iron metabolism and maintain iron homeostasis in the human body. Management of iron metabolism requires complex and fine coordination of various proteins, and the more important ones are Ft [5], TF [6], hepcidin [8], and various iron ion regulatory proteins [7].…”