Influence of At1r Polymorphisms and Aerobic Exercise Training on Angiotensin Ii, Oxidative Stress and Nitric Oxide

Title of Document: INFLUENCE OF AT1R POLYMORPHISMS AND AEROBIC EXERCISE TRAINING ON ANGIOTENSIN II, OXIDATIVE STRESS AND NITRIC OXIDE Nicola Melissa Fenty, Doctor of Philosophy, 2007 Directed By: Professor, James M. Hagberg, Department of Kinesiology Oxidative stress is implicated in the pathogenesis of cardiovascular disease (CVD) and angiotensin II (AngII), via the type 1 receptor (AT1R), is a major factor contributing to oxidative stress. Protection against oxidative injury is provided by several antioxidants, including superoxide dismutase (SOD). Aerobic exercise training (AEX) is a non-pharmacological intervention that reduces the risk of CVD, partly through reducing levels of oxidative stress. We investigated whether the AT1R A1166C and -825 T/A polymorphisms and AEX influence oxidative stress, urinary NOx and plasma AngII. One hundred sedentary, hypertensive individuals underwent 6 months of standardized AEX. Plasma levels of AngII and SOD, and urinary excretion of NOx and 8-iso-PGF2α were measured before and after AEX. Subject characteristics and baseline values of outcome variables were similar among all genotype groups. Overall, there was a significant increase in 8-iso-PGF2α (p = 0.002) and a significant decrease in NOx excretion (p = 0.0001) however, there were no significant changes in SOD activity or AngII levels with AEX. Neither oxidative stress markers nor urinary NOx were significantly different between genotype groups with AEX. There was a significant difference in AngII levels with AEX between A1166C genotype groups (p = 0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEX on the change in AngII (p < 0.05). The TT genotype group of the -825 T/A polymorphism had a significant reduction (p = 0.02) in plasma AngII, while there was no change in carriers of the A allele. Risk allele analysis revealed that there was a significant reduction in plasma AngII (p = 0.04), a significant increase in 8-iso-PGF2α (p = 0.01) and a significant decrease in urinary NOx (p = 0.0001) with AEX in individuals with 2 risk alleles. Our findings suggest that variation in the AT1R gene is associated with differential changes in plasma AngII but not with oxidative stress. Furthermore, our results may have clinical implications for the prescription of AEX in a population at risk for CVD as exercise intensities that surpass moderate intensity, may attenuate some of the beneficial effects of regular exercise by leading to increased oxidative stress. INLFUENCE OF AT1R POLYMORPHISMS AND AEROBIC EXERCISE TRAINING ON ANGIOTENSIN II, OXIDATIVE STRESS AND URINARY NITRIC OXIDE.