Evidence for a relationship between mitochondrial Complex I activity and mitochondrial aldehyde dehydrogenase during nitroglycerin tolerance: Effects of mitochondrial antioxidants

Autores de FISABIO

• Remedios Garcia Bou

  Autor

• 

  Milagros Rocha Barajas

  Autor

• 

  Nadezda Apostolova Atanasovska

  Autor

• Jose Raul Herance Camacho

  Autor

• Antonio Hernández Mijares

  Autor

• Victor Manuel Victor González

  Autor

Grupos de Investigación

• GRUPO 008. MECANISMOS MOLECULARES SUBYACENTES A LA DIABESIDAD

  

  Investigador/a Principal

  Milagros Rocha Barajas

Abstract

The medical use of nitroglycerin (GTN) is limited by patient tolerance. The present study evaluated the role of mitochondrial Complex I in GIN biotransformation and the therapeutic effect of mitochondrial antioxidants. The development of GIN tolerance (in rat and human vessels) produced a decrease in mitochondrial 02 consumption. Co-incubation with the mitochondria-targeted antioxidant mitoquinone (MQ 10(-6) mol/L) or with glutathione ester (GEE, 10(-4) mol/L) blocked GTN tolerance and the effects of GTN on mitochondrial respiration and aldehyde dehydrogenase 2 (ALDH-2) activity. Biotransformation of GTN depended on the mitochondria being functionally active, particularly mitochondrial Complex I. Tolerance induced mitochondrial ROS production and oxidative stress, though these effects were not detected in HUVEC rho(0) cells or Complex I mutant cells. Experiments performed to evaluate Complex I-dependent respiration demonstrated that its inhibition by GIN was prevented by the antioxidants in control samples. These results point to a key role for mitochondrial Complex I in the adequate functioning of ALDH-2. In addition, we have identified mitochondrial Complex I as one of the targets at which the initial oxidative stress responsible for GIN tolerance takes place. Our data also suggest a role for mitochondrial-antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use. (C) 2012 Elsevier B.V. All rights reserved.

Keywords

• Oxidative stress; Nitric oxide; Nitroglycerin; Mitochondria; ALDH-2; Antioxidant