Key result
Angiotensin receptor blockade with olmesartan increased Nrf2 binding by 32% and improved mitochondrial enzyme activities in obese insulin-resistant rats following an acute glucose load.
Why the study?
Does olmesartan improve cardiac mitochondrial activity in response to an acute glucose load in obese insulin-resistant rats?
Does olmesartan improve cardiac mitochondrial activity in response to an acute glucose load in obese insulin-resistant rats?
Effect estimate: 32% increase in Nrf2 binding
AT1 blockade with olmesartan protects cardiac mitochondrial function during insulin resistance, likely via upregulation of Nrf2 and subsequent antioxidant activities.
Hypothesis-generating for AT1-Nrf2 mitochondrial protection in insulin-resistant hearts; does not yet inform clinical practice.
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.
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Thorwald et al. (2017) studied Insulin resistance and obesity. Angiotensin receptor blocker (olmesartan) vs. OLETF (untreated obese insulin-resistant rats) and LETO (lean controls) was evaluated on Nrf2 binding and mitochondrial enzyme activities (32% increase in Nrf2 binding). Angiotensin receptor blockade with olmesartan increased Nrf2 binding by 32% and improved mitochondrial enzyme activities in obese insulin-resistant rats following an acute glucose load.
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