Mitochondrial Electron Transport Complex I Is a Potential Source of Oxygen Free Radicals in the Failing Myocardium

Abstract

Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4-hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5,5-dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH-ubiquinone oxidoreductase (complex I) and succinate-ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P0.01) in HF, which was due to the functional block of electron transport at complex I. The enzymatic activity of complex I decreased in HF (27413 versus 1369 nmol min 1 mg 1 protein, P0.01), which may thus have caused the functional uncoupling of the respiratory chain and the deleterious ROS production in HF mitochondria. The present study provided direct evidence for the involvement of ROS in the mitochondrial origin of HF myocytes, which might be responsible for both contractile dysfunction and structural damage to the myocardium. (Circ Res. 1999;85:357-363.) Key Words: antioxidant free radical heart failure myocardial contraction reactive oxygen species C ongestive heart failure (HF) is an important cause of morbidity and mortality in patients with various heart diseases. Despite extensive studies, the fundamental mechanisms responsible for the development and progression of left ventricular (LV) failure have not yet been fully elucidated. Reactive oxygen species (ROS) such as superoxide anions (O 2) and hydroxy radicals (OH) cause the oxidation of membrane phospholipids, proteins, and DNAs, and they have been implicated in a wide range of pathological conditions including ischemia-reperfusion injury, neurodegenerative diseases , and aging. Under physiological conditions, their toxic effects are prevented by such scavenging enzymes as super-oxide dismutase (SOD), glutathione peroxidase, and catalase as well as by other nonenzymatic antioxidants. However, when the production of ROS becomes excessive, oxidative stress might have a harmful effect on the functional integrity of biological tissue. Oxygen free radicals have been shown to cause contractile failure and structural damage in the myo-cardium. 1,2 However, their significance has been demonstrated to limited subsets of cardiac diseases, which include ischemic heart disease 3 and adriamycin-induced cardiac toxicity. 4 Recent investigations have suggested the generation of ROS to increase in chronic HF. Lipid peroxides and 8-iso-prostaglandin F 2 , which are the major biochemical consequences of RO...

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

“…The proangiogenic role of Nox4 involves a paracrine mechanism in which Nox4 up-regulation in cardiomyocytes leads to enhanced Hif1 activation and increased release of VEGF, which in turn promotes capillarization. The beneficial effects of Nox4 contrast markedly with those of other ROS sources in the remodeling heart, such as mitochondria, which have been found to be detrimental and have formed the basis for the testing of antioxidant therapies in human heart failure (29,30). Our findings, however, indicate that therapeutic strategies may need to be directed toward specific ROS sources and pathways rather than the nonspecific targeting of ROS.…”

Oxidative Stress in Heart Failure: The Role of Mitochondria.

“…Skeletal muscle mitochondria from HFare associated with a decrease in the complex I and III activities (29). As has been shown in the failing hearts (8), the defects in electron transfer function may lead to the ROS production. ROS may play an important role in the muscle atrophy commonlyseen in HF patients through the induction of apoptosis.…”

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

“…Potential vascular sources of O 2 −• include xanthine oxidase (XO), cyclooxygenase, uncoupling of NO synthases (NOS) [11,[41][42][43][44], and NAD(P)H oxidases (multisubunit membrane complexes) [42], as well as the mitochondrial respiratory chain [45] and hemoglobin [46,47], the relative importance of which may vary among vascular beds, types of cells, and disease conditions. Recent studies suggest that in coronary arteries, NAD(P)H oxidases of the NOX family are a predominant source of O 2 −• from noninflammatory cells such as endothelium [48,49].…”