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

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

Virtual

Congreso; V CONGRESO INTERNACIONAL EN MEDICINA TRASLACIONAL ? MAESTRIA EN CIENCIAS BIOMEDICAS (IMBS); 2021

Background: Insulin signaling is essential for normal mitochondrial function in cardiomyocytes. Hydrogen peroxide (H2O2), the main metabolite effective in redox sensing, signaling and regulation, has been described as an "insulinomimetic" agent. While physiological H2O2 steady-state concentration ([H2O2]ss) is about 1?10 nM, higher [H2O2]ss lead to adaptive stress responses, and supraphysiological [H2O2]ss (>100 nM) lead to oxidative distress. In addition, nitric oxide (NO) also participates in redox signaling, with these species connected in mitochondrial matrix, through the reaction between O2- and NO yielding peroxynitrite (ONOO-). Aim: To study heart mitochondrial H2O2 and NO metabolism in 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 the mitochondrial function, reactive species production and redox status were evaluated. Results: Concerning mitochondrial functionality, only the state 3 respiration sustained by malate+glutamate and complex I activity were reduced (23% and 17%), without changes in the respiration sustained by succinate and in the complexes II, III, and IV activities. Moreover, neither the membrane potential, ATP production, nor ADP/O was different between groups. Although [GSSG+GSH]mitochondrial was lower in diabetic rats, there was no difference in GSH/GSSG. Mitochondrial H2O2 production was 117% higher in diabetic group. However, this increase was accompanied by an enhancement in the H2O2 detoxification enzymes activities and 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 mtNOS expression (29%) were also increased. Consequently, lipid peroxidation evaluated from 4-HNE expression (45%), and tyr-nitration (42%) were higher in the heart mitochondria of diabetic animals. Conclusions: The conservation of mitochondrial membrane potential, ATP generation, and ADP/O and GSH/GSSG ratios suggest the absence of irreversible damage after 7 days of hyperglycemia. The increase in mitochondrial [H2O2]ss above the physiological range, but still below supraphysiological concentrations seems to be part of the adaptive response, triggered in cardiomyocytes, due to the absence of insulin. However, if insulin deficiency persists cardiomyocytes shifts into oxidative distress.