Heart mitochondrial H2O2 and NO metabolism in an early stage of Diabetes 1.

RUKAVINA MIKUSIC IA; REY M; ADAN AREAN JS; VANASCO V; ALVAREZ S; VALDEZ LB

Virtual

Congreso; V International Congress in Translational Medicine. International Master Program in Biomedical Sciences (IMBS).; 2021

International Master Program in Biomedical Sciences (IMBS)

Background: Insulin signaling is essential for normal mitochondrial functionin cardiomyocytes. Hydrogen peroxide (H2O2) -the mainmetabolite effective in redox sensing, signaling and regulation- has beendescribed as an "insulinomimetic" agent. While physiological H2O2steady-state concentration ([H2O2]ss) is about1?10 nM, higher [H2O2]ss lead to adaptivestress responses, and supraphysiological [H2O2]ss(>100 nM) lead to oxidative distress. In addition, nitric oxide (NO) also participatesin redox signaling, with these species connected in mitochondrial matrix, throughthe reaction between O2- and NO yielding peroxynitrite (ONOO-).Aim: To study heart mitochondrial H2O2 and NO metabolismin an early stage of type 1 diabetes. Methods: Diabetes was induced by a single dose of Streptozotocin (60 mg/kg,ip.) in male rats (glycemia after 72 h: 130±5 (Control) vs. 415±23 (Diabetes)mg/dl). The animals were sacrificed at day 10, the hearts were removed, and themitochondrial function, reactive species production and redox status wereevaluated. Results: Concerning mitochondrial functionality, only the state 3respiration sustained by malate+glutamate and complex I activity were reduced (23%and 17%), without changes in the respiration sustained by succinate and in the complexesII, III, and IV activities. Moreover, neither the membrane potential nor ATPproduction -determined through luciferin/luciferase technique or ADP/O ratio- weredifferent between groups. Although [GSSG+GSH]mitochondrial was lowerin diabetic rats, there was no difference in GSH/GSSG. Mitochondrial H2O2production was 117% higher in diabetic group. However, this increase was accompaniedby an enhancement in the H2O2 detoxification enzymes activitiesand expressions: catalase (200% and 233%) and glutathione peroxidase (26% and 42%),leading to [H2O2]ss ~50 nM. NO and ONOO- productions (30% and 225%) and mtNOSexpression (29%) were also increased. Consequently, lipid peroxidation (45%)       -evaluated from 4-HNE expression- andtyr-nitration (42%) were higher in the heart mitochondria of diabetic animals. Conclusions: The conservation of mitochondrial membrane potential, ATPgeneration, and ADP/O and GSH/GSSG ratios suggest the absence of irreversible damageafter 7 days of hyperglycemia. The increase in mitochondrial [H2O2]ssabove the physiological range, but still below supraphysiologicalconcentrations seems to be part of the adaptive response, triggered in cardiomyocytes,due to the absence of insulin. However, if insulin deficiency persists, cardiomyocytesshifts into oxidative distress.