Antioxidant pyruvate inhibits cardiac formation of reactive oxygen species through changes in redox state

Abstract

Myocardial ischemia-reperfusion is associated with bursts of reactive oxygen species (ROS) such as superoxide radicals (O(2)(-).). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O(2)(-)., implying the NADH concentration-to-NAD(+) concentration ratio ([NADH]/[NAD(+)]) as a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS formation were measured as influenced by pyruvate or L-lactate. Pre- and postischemic Langendorff guinea pig hearts were perfused at different pyruvate/L-lactate concentrations to alter cytosolic [NADH]/[NAD(+)]. NADHox and ROS were measured with the use of lucigenin chemiluminescence and electron spin resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 mM) and the NADHox blocker hydralazine markedly inhibited NADHox (16 +/- 2%, 58 +/- 9%). In postischemic hearts, pyruvate (0.1-5.0 mM) dose dependently inhibited ROS up to 80%. However, L-lactate (1.0-15.0 mM) stimulated both basal and postischemic ROS severalfold. Furthermore, L-lactate-induced basal ROS was dose dependently inhibited by pyruvate (0.1-5.0 mM) and not the xanthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xanthine oxidase. The data suggest a substantial influence of cytosolic NADH on cardiac O(2)(-). formation that can be inhibited by submillimolar pyruvate. Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be alleviated by redox reactants such as pyruvate.

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

“…The observation of NADH-induced ROS production in our study is consistent with others (27)(28)(29)(37)(38)(39). However, the mechanism is not well understood.…”

“…It is also observed in patients with metabolic syndrome, diabetes, congestive heart failure, and various other diseases (34 -36). In a study of ischemia/reperfusion in the isolated guinea pig heart, Bassenge et al (37) showed that lactate stimulated ROS production severalfold, whereas pyruvate inhibited postischemic ROS production up to 80% in a dose-dependent way. The finding that lactate or cytosolic NADH induce an increase in ROS and inhibit I NCX may shed light on oxidative stress and abnormal Ca 2ϩ handling in the heart under these conditions.…”

Identification of pyruvate kinase as an antigen associated with Tourette syndrome

“…It is also known that dendritic cells presenting PK M1/M2 isozyme peptide can induce experimental allergic myositis in BALB/c mice (Kawachi et al, 2001). Tissue damage during myocardial ischemia/reperfusion can be reduced by the administration of pyruvate (Bassenge et al, 2000), and pyruvate, being a scavenger of hydrogen peroxide thereby reduces excessive production of free radicals, a process that has been implicated in the pathology of several neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.…”

The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells

“…The mechanism by which UCP-2 overexpression decreases NAD(P)H oxidase activity is presently unknown, but may be due to its effect on the cellular NADH/NAD + redox state. Bassenger et al reported that reduction of the NADH concentration : NAD + concentration ratio (NADH : NAD + redox) by pyruvate infusion dose-dependently inhibited NAD(P)H oxidase activity and ROS generation in perfused guinea pig hearts [30]. Therefore, it can be assumed that high-glucose-and Ang-II-induced mitochondrial membrane hyperpolarisation, which reflects impairment of mitochondrial electron transfer and respiration, would increase NAD(P)H oxidase activity by increasing the cytosolic NADH : NAD + ratio.…”