Biography

Biography: Abeer M. Mahmoud

Abstract

Obesity-associated Hypoxia Contributes to Aberrant Methylation of Genes Implicated in Inflammation and vascular Function

Abeer M. Mahmoud

University of Illinois, USA

Abstract

Introduction: Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity-associated hypoxia in disturbing the methylation/expression of genes involved in inflammation/vascular function. We also propose a mediating role of the hypoxia-inducible factor, HIF1α and the DNA hydroxymethylase, TET1.

Methods: We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non-obese (NOB) adults having elective surgeries (n=30; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to pressure gradients of ∆10-∆100 cmH₂O. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and methylation/expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNÉ£ were measured in the AT.

Results: Flow-induced dilation (FID) was 40-50% higher in NOB than OB adults across all pressure gradients (p<0.05). NO production was higher, and ROS generation was lower in OB arterioles compared to NOB. HIF1α and TET1 proteins were 2-4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID, NO, and brachial artery FID (r=0.82, 0.64, 0.91, respectively; p<0.001) and positively with ROS (r=-0.71, p<0.01). Global hydroxymethylation and adipocytokine promoter hypomethylation and increased expression were observed in OB compared to NOB.

Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines. This conclusion was also supported by invitro mechanistic studies.