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 of genes involved in inflammation and vascular dysfunction and 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=36; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to increasing pressure gradients. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and promoter methylation/gene expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNɣ were measured in the AT biopsy. Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound.
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 the OB arterioles compared to NOB. HIF1α and TET1 proteins were 2 to 4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID and NO and brachial artery FMD (r=0.82, 0.64, 0.91, respectively; p<0.001) and positively with arteriolar ROS production (r=-0.71, p<0.01). Global hydroxymethylation was observed in OB compared to NOB as well as DNA promoter hypomethylation and increased gene expression of the targeted adipocytokines.
Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines in the hypoxic AT. A downstream target for this pathway could reside in endothelial cells of nearby arterioles and remote arteries resulting in vascular dysfunction.
M.M. Ali: None. C. Hassan: None. M. Masrur: None. F. Bianco: Consultant; Self; Intuitive, Medtronic. S.A. Phillips: None. A.M. Mahmoud: None.
National Institutes of Health (4R00HL140049, 031K99, HL14004901)