Effects of Losartan on Oxidative Stress, DNA Damage, and Metabolic Parameters in Whole Blood and Liver of Rhesus Monkeys (Macaca mulatta)

Abstract

Angiotensin II (Ang II), the primary peptide of the Renin Angiotensin System (RAS), can induce the production of reactive oxygen species (ROS) and affect mitochondrial energetics, predisposing to age‐related disorders. Angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) can attenuate ROS production, improve mitochondrial function and increase survival in aging rodents, however, the effects of losartan, an ARB, on age‐associated oxidative damage in rhesus monkeys have not been yet explored. We have previously shown that mitochondrial DNA (mtDNA) damage, depletion of mtDNA molecules and oxidative stress increase in liver and blood leukocytes of middle‐age and old rhesus monkeys. We hypothesize that losartan treatment prevents oxidative damage in liver and blood leukocytes from rhesus monkeys. To test our hypothesis we examined the effects of losartan on mtDNA, nuclear DNA (nDNA) and protein damage, mtDNA abundance in whole blood and liver and metabolic parameters in losartan‐treated and age‐matched untreated middle‐age rhesus monkeys. Middle‐age rhesus monkeys (8–19 years of age) were treated with losartan (30mg/day) for 12 months and samples were obtained at baseline, 3, 6, and 12 months after treatment. Young (3–6 years of age) untreated monkeys were also analyzed as a control for the effects of aging. Fasting insulin and fasting glucose were measured in the serum and mitochondrial DNA (mtDNA) damage and abundance, and nuclear DNA (nDNA) damage were assessed by quantitative PCR. Protein carbonylations were measured in peripheral blood mononuclear cells (PBMCs) and liver of rhesus monkeys using the FTC Fluorometric assay. Interestingly, we found that losartan significantly decreased fasting blood glucose levels in healthy middle‐age monkeys after 12 months of treatment when compared to age‐matched untreated animals. No effects were observed on systolic/diastolic blood pressure, fasting insulin, cholesterol, tryglycerides and glycated hemoglobin levels. In whole blood samples, middle‐age monkeys exhibit significant increased levels of nDNA lesions compared to young animals, and treatment with losartan decreased nDNA damage to levels similar to young animals. Moreover, we found a significant decrease in the levels of carbonylated proteins in PBMCs from middle‐age monkeys treated with losartan compared to untreated monkeys, indicative of lower levels of oxidative stress. No significant differences were observed in the levels of mtDNA copies between the groups. In liver, middle‐age monkeys exhibited decreased levels of mtDNA molecules and losartan had no effect on preventing the loss of mtDNA copies. In contrast to PBMCs, no significant differences were observed in nDNA lesions and protein carbonylations between groups. Surprisingly, losartan significantly increased the levels of mtDNA damage as compared to young animals. Collectively, our results suggest that losartan precludes nDNA (but not mtDNA) and protein oxidative damage in PBMCs (but not in liver) and improves glucose levels in healthy middle‐age rhesus monkeys.Support or Funding InformationP40RR003640R25 GM061838U54 MD007600This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.