AT1 Receptor Blockade Improves Mitochondrial Activity in Insulin Resistant but not Type II Diabetic Hearts

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 through NAPDH assemblage. To test the acute effects of an oral glucose tolerance test (oGTT) on the insulin resistant and type II diabetic hearts, 16 and 25 week old animals were given a glucose tolerance test prior to dissection. Adult male rats were randomly assigned to three groups prior to dissection (n= 5–8 animals/group/time point): 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; 10 mg olmesartan/kg/d x 6–8 weeks). Hearts were collected at T0, T60, and T120 minutes post‐glucose infusion and at T0, T180, and T360 in 25‐week‐old animals. Aconitase activity was not changed between LETO and OLETF rats at T0, but was increased five‐fold with ARB treatment. At T60 aconitase activity was decreased 69% in OLETF from LETO, but ARB treatment increased activity six‐fold. AT 25 weeks of age aconitase activity was two‐fold higher in OLETF compared to LETO and remained unchanged through T360. ARB treatment lowered this activity to LETO levels at T0 only. Complex I activity had no detectable difference between LETO and OLETF in 16 week old animals; however, ARB increased activity by 50%. However, in 25 week old animals complex I was lowered 32% from LETO and ARB treatment had no effect on complex I activity. At T60, complex II activity was decreased 30% from LETO in OLETF rats, and ARB treatment increased complex II activity by 79%. In 25 week old animals OLETF rats had increased complex II activity at T180 by 34%, which then was restored to baseline by T360. ARB treatment increased activity by 26%, but maintained this increase over the 6 hour span. These data demonstrate the protective effects of AT1 blockade on cardiac mitochondrial function during the manifestation of insulin resistance, but demonstrate that its protective effects diminish as animals transition into a frank diabetic stage.Support or Funding InformationM. Thorwald and R. Rodriguez were supported by NIH NCMHD9T37MD001480. R.M. Ortiz was partially supported by NIH NHLBIK02HL103787. Research was partially funded by NIH NHLBIR01HL091767.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.