H2O2, NO and ONOO- in the cardiac mitocondrial dysfunction in a type 1 Diabetes model

RUKAVINA MIKUSIC IA; REY M; BOMBICINO SS; VALDEZ LB

Virtual

Congreso; Reunión de las Sociedades de Biociencias 2020; 2020

SAIC- SAI - SAFIS

AIM: To study the changes of mitochondrial production rates and/or steady-state concentrations ([X]ss) of O2-, H2O2, NO and ONOO- in the temporal evolution of cardiac mitochondrial dysfunction in a type 1 diabetes model. METHODS: Diabetes was induced by a single dose of Streptozotocin (STZ, 60 mg/kg, ip) in male rats. Glycemia (mg/dl) was determined after 72 h (C:130±5; DM:415±23). The animals were sacrificed after 10 or 28 days of STZ-injection (7 or 25 days of hyperglycemia). Mn-SOD activity, and H2O2 and NO production rates were determined in the cardiac mitochondrial fraction. [O2-]ss,[NO]ss and ONOO- generation were estimated from experimental data. RESULTS: When animals were sacrificed 10 days after STZ-injection, heart mitochondrial NO (30%) and H2O2 (117%) productions were higher and Mn-SOD activity was lower (15%) than control values. Moreover, mitochondrial [O2-]ss was 2.5-fold higher in heart from diabetic rats, along with a 30% increase in [NO]ss. Thus, ONOO- production rate resulted 3 times higher. When animals were subjected to 25 days of hyperglycemia, Mn-SOD activity was really reduced (50%). While H2O2 generation was extremely augmented (128%), the increase in NO generation (23%) was similar to the one observed at 7 days. Increases in [O2-]ss (350%), [NO]ss (25%), and ONOO- production (450%) were obtained. Moreover, nitration of tyrosine residues of mitochondrial proteins was observed in diabetic animals sacrificed at day 28. CONCLUSIONS: Heart mitochondrial production rates of H2O2, NO and ONOO- were higher in diabetic than in control animals, both after 7 and 25 days of hyperglycemia. No difference in the increase -over the control values- of [NO]ss was observed over time, while a much greater rise in [O2-]ss was detected after 25 days of sustained hyperglycemia respect to the enhancement obtained at 7 days, intensifying the difference in ONOO- generation. Therefore, ONOO- generation rate is mainly controlled by [O2-]ss rather than by [NO]ss