Abstract
Hyperglycemia increases the risk of oxidant overproduction in the heart through activation of a multitude of pathways. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer, contributing to mitochondrial dysfunction. Furthermore, the renin-angiotensin system (RAS) becomes inappropriately activated during metabolic syndrome, increasing oxidant production. To combat excess oxidant production, the transcription factor, nuclear factor erythriod-2- related factor 2 (Nrf2), induces expression of many antioxidant genes. We hypothesized that angiotensin II receptor type 1 (AT1) blockade improves mitochondrial function in response to an acute glucose load via upregulation of Nrf2. To address this hypothesis, an oral glucose challenge was performed in three groups prior to dissection (n = 5–8 animals/group/time point) of adult male rats: 1) Long Evans Tokushima Otsuka (LETO; lean strain-control), 2) insulin resistant, obese Otsuka Long Evans Tokushima Fatty (OLETF), and 3) OLETF + angiotensin receptor blocker (ARB; 10mg olmesartan/kg/d × 6 weeks). Hearts were collected at T0, T60, and T120 minutes post-glucose infusion. ARB increased Nrf2 binding 32% compared to OLETF at T60. Total superoxide dismutase (SOD) and catalase (CAT) activities were increased 45% and 66% respectively in ARB treated animals compared to OLETF. Mitochondrial enzyme activities of aconitase, complex I, and complex II increased by 135%, 33% and 66%, respectively in ARB compared to OLETF. These data demonstrate the protective effects of AT1 blockade on mitochondrial function during the manifestation of insulin resistance suggesting that the inappropriate activation of AT1 during insulin resistance may impair Nrf2 translocation and subsequent antioxidant activities and mitochondrial function.
Highlights
Metabolic syndrome is a rising epidemic in the western world and is characterized by the simultaneous presence of hypertension, dyslipidemia, elevated fasting plasma glucose levels, abdominal obesity, and insulin resistance [11]
Systolic blood pressure and body mass measurements were taken at the end of the study to observe the status of metabolic syndrome in OLETF rats and to confirm the effectiveness of the angiotensin receptor blockade (ARB)
The factors contributing to the development of insulin resistance are not well known nor is the impact that insulin resistance has on mitochondrial function
Summary
Metabolic syndrome is a rising epidemic in the western world and is characterized by the simultaneous presence of hypertension, dyslipidemia, elevated fasting plasma glucose levels, abdominal obesity, and insulin resistance [11]. Insulin resistance (IR) is a hallmark for the progression of type II diabetes and causes an incomplete uptake of circulating plasma glucose due to impaired insulin secretion and/or receptor signaling [1]. Mitochondrial dysfunction contributes to heart disease, and may contribute disproportionately to the accumulation of oxidative damage during diabetes [2,19]. Cardiomyocytes contain larger amounts of mitochondria compared to other tissues [27], while the heart as a whole contains a lower antioxidant capacity [33] which increases its susceptibility to mitochondria-derived oxidation. Mitochondrial oxidation increases oxidant generation further burdening antioxidant enzymes, which may lessen their ability to correct the oxidant imbalance [14]. Mitochondrial and antioxidant dysfunctions may be exacerbated by post-prandial glucose mediated oxidant production in insulin resistant individuals [3,34]. Among the enzymes that are altered by oxidized conditions are aconitase, and in the citric acid cycle, NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), and cytochrome c reductase (complex III) [4,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
