Heart mitochondrial nitric oxide synthase. Effects of hypoxia and aging.

VALDEZ LB; ZAOBORNYJ T; ALVAREZ S; BUSTAMANTE J; COSTA LE; BOVERIS A

Mol Aspects Med

Elsevier Ltd - Pergamon

Año: 2004 vol. 25 p. 49 - 59

The production of NO by heart mitochondria was 0.7-1.1 nmol NO/min. mg protein, an activity similar to the ones observed in mitochondrial membranes from other organs. Heart mtNOS seems to contribute with about 56 % of the total cellular NO production. The immunological nature of the mtNOS isoform of cardiac tissue remains unclear; in our laboratory, heart mtNOS reacted with an anti-iNOS antibody. Heart mtNOS expression and activity are regulated by physiological and pharmacological effectors. The state 4/state 3 transition regulates heart mtNOS activity and NO release in intact respiring mitochondria: NO production rates in state 3 were 40 % lower than in state 4. Heart mtNOS expression was selectively regulated by O2 availability in hypobaric conditions and the activity was 20-60% higher in hypoxic rats than in control animals, depending on age. In contrast, NADH-cytochrome c reductase and cytochrome oxidase activities were not affected by hypoxia. The activity of rat heart mtNOS decreased 20 % on aging from 12 to 72 wk of age. On the pharmacological side, mitochondrial NO production was increased after enalapril treatment (the  inhibitor of the angiotensin converting enzyme) with modification of heart mtNOS functional activity in the regulation of mitochondrial O2 uptake and H2O2 production. Thus, heart mtNOS is a highly regulated mitochondrial enzyme, which in turn, plays a regulatory role through  mitochondrial NO steady state levels that modulate O2 uptake and O2- and H2O2 production rates. Nitric oxide and H2O2 constitute signals for metabolic control that are involved in the regulation of cellular processes, such as proliferation and apoptosis.