Endogenous Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Is a Physiological Regulator of Myocardial Oxygen Consumption

Loke, Kit E.; McConnell, Patrick I.; Tuzman, Joshua; Shesely, Edward G.; Smith, Carolyn J.; Stackpole, Christopher J.; Thompson, Carl I.; Kaley, Gabor; Wolin, Michael S.; Hintze, Thomas H.

doi:10.1161/01.res.84.7.840

Cited by 165 publications

(128 citation statements)

References 45 publications

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“…It has been demonstrated that an acute bout of exercise enhances the production of NO, and thereby contributes to skeletal muscle vasodilatation [4,21]. NO is involved in cardioprotection [20], myocardial respiration [15,16], and in insulin-independent glucose uptake into the working muscle fibres [17]. This molecule also modulates the kinetics of oxygen consumption during exertion [29].…”

Section: Introductionmentioning

confidence: 99%

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

et al. 2012

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The NOS3-786 T/C polymorphism (rs2070744) is a candidate to explain individual variations in sports related phenotypes. We determined the genotype and allele frequency of NOS3-786 T/C in a group of 60 male professional elite soccer players.Their results were compared with those of 100 world-class endurance athletes, 53 elite power athletes, and 100 sedentary, healthy men (controls) of the same Caucasian (Spanish) origin. There were significant differences in genotype frequencies between soccer players, controls, endurance and power elite athletes (all P≤0.02). These results were confirmed when we analysed allelic frequencies (all P<0.01). The likelihood of having the C allele was higher in soccer players compared with (i) controls [odds ratio (OR), 2.165, 95% confidence interval (CI): 1.362-3.441], (ii) endurance athletes (OR:1.879, 95%CI: 1.184-2.984), and (iii) power athletes (OR: 4.032, 95%CI: 2.307-7.047). In conclusion, the -786C allele is associated with the status of being an elite soccer player, compared with non-athletic controls and also with elite endurance and power athletes. More research is needed in other groups of elite soccer players in order to replicate the results of the present study.

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Section: Introductionmentioning

confidence: 99%

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

et al. 2012

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“…Mitochondrial respiration is under tonic inhibitory control of NO in accord with the finding that inhibition of NOS invariably increases mitochondrial oxygen consumption (28). Hence, insights into the topology of the enzyme in relation to the respiratory chain are crucial for understanding regulatory mechanisms of NO action.…”

Section: Discussionmentioning

confidence: 75%

Docking of Endothelial Nitric Oxide Synthase (eNOS) to the Mitochondrial Outer Membrane

Gao

Chen

Brodsky

et al. 2004

Journal of Biological Chemistry

112

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Despite growing evidence for a mitochondrial localization of nitric oxide (NO) synthase and a broadening spectrum of NO actions on mitochondrial respiration and apoptosis, the basis for interaction between the enzyme and the organelle remain obscure. Here we investigated mitochondrial localization of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells and human embryonic kidney cells transfected or infected with eNOS expression vectors. Copurification of eNOS with mitochondria was observed in both human umbilical vein endothelial cells and eNOSexpressing human embryonic kidney cells. Immunodetectable eNOS was cleaved from mitochondria by proteinase K treatment, suggesting eNOS association with the outer mitochondrial membrane. Localization of eNOS to a proteinase K-cleavable site on the cytoplasmic face of the outer membrane was confirmed by immunogold labeling of non-permeabilized mitochondria. Markers for mitochondrial subfractions ruled out the possibility of eNOS association with an intramitochondrial site or inverted mitochondrial particles. Denaturation of eNOS did not attenuate association with mitochondria. Mutant eNOS lacking a pentabasic amino acid sequence within the autoinhibitory domain (residues 628 -632 of the bovine eNOS) showed dramatically reduced binding to the mitochondrial but not to the plasma membrane, which was associated with increased oxygen consumption. Collectively, these findings argue in favor of eNOS localization to the outer mitochondrial membrane in endothelial cells and identify elements of a novel anchoring mechanism.An association of NOS-like proteins with mitochondria has previously been demonstrated immunohistochemically (1-4). Further supporting evidence was provided by the partial purification of mitochondrial nitric oxide synthase (mtNOS) 1 activity (5, 6). There is an ongoing debate as to the identity of mtNOS; immunologic cross-reaction of mtNOS with antibodies against endothelial NOS (eNOS) (1, 3, 7), neuronal NOS (4), and inducible NOS (6) have been reported. A recent investigation (8) has identified a neuronal NOS in cardiomyocyte mitochondria. It has been suggested that mtNOS plays important roles in oxidative stress and apoptosis (9, 10), regulation of mitochondrial respiration (11,12), and modulation of intracellular Ca 2ϩ homeostasis (13).The potential distribution of mtNOS in subfractions of mitochondria has been explored but remains enigmatic. Some indirect evidence suggests that mtNOS is localized to the inner mitochondrial membrane. Indeed, immunohistochemical findings suggest that mtNOS co-localizes with succinate dehydrogenase, a mitochondrial marker for the inner membrane (2). Further support for an inner membrane localization of NOS in mitochondria came from NOS activity assays, which indicated that specific activity in submitochondrial particles and crude fractions was higher than that of mitochondrial homogenates or permeabilized mitochondria (14). In contrast, a recent report (15) suggested that eNOS localizes to the oute...

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“…It is known that Bk activates eNOS in endothelial cells by way of the B 2 receptors and decreases mitochondrial respiration (Loke et al 1999). Likewise, Ca 2+ ionophore III enhances the production of NO by calmodulindependent binding, thus lowering the respiration rate.…”

Section: Resultsmentioning

confidence: 99%

“…Previously reported studies have found that the activation of the NOS enzyme during oxygen consumption measurements in endothelial cells (Loke et al 1999;Palacios-Callender et al 2004) and cardiac myocytes (Dai et al 2001) reduced the V O 2 max and increased p50. However, the results obtained in the present studies for BAECs pre-incubated with NOS stimulators or inhibitors exemplify different results.…”

Section: Hsp90mentioning

confidence: 89%

“…Among these isoforms, eNOS has been shown to play a prominent role in the regulation of cellular respiration due to its high abundance (Ilangovan et al 2004a;Loke et al 1999;Palacios-Callender et al 2004). Moreover, eNOS is activated by heat shock protein 90 (Hsp90) by forming an Hsp90/eNOS complex, and hence, eNOS activation through S-1179 phosphorylation is facilitated (Averna et al 2008;Harris et al 2008;Presley et al 2008;Pritchard et al 2001;Song et al 2002;Xu et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Activation of Hsp90/NOS and increased NO generation does not impair mitochondrial respiratory chain by competitive binding at cytochrome C Oxidase in low oxygen concentrations

Presley

Vedam

et al. 2009

Cell Stress and Chaperones

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Nitric oxide (NO) is known to regulate mitochondrial respiration, especially during metabolic stress and disease, by nitrosation of the mitochondrial electron transport chain (ETC) complexes (irreversible) and by a competitive binding at O 2 binding site of cytochrome c oxidase (CcO) in complex IV (reversible). In this study, by using bovine aortic endothelial cells, we demonstrate that the inhibitory effect of endogenously generated NO by nitric oxide synthase (NOS) activation, by either NOS stimulators or association with heat shock protein 90 (Hsp90), is significant only at high prevailing pO 2 through nitrosation of mitochondrial ETC complexes, but it does not inhibit the respiration by competitive binding at CcO at very low pO 2 . ETC complexes activity measurements confirmed that significant reduction in complex IV activity was noticed at higher pO 2 , but it was unaffected at low pO 2 in these cells. This was further extended to heat-shocked cells, where NOS was activated by the induction/activation of (Hsp90) through heat shock at an elevated temperature of 42°C. From these results, we conclude that the entire attenuation of respiration by endogenous NO is due to irreversible inhibition by nitrosation of ETC complexes but not through reversible inhibition by competing with O 2 binding at CcO at complex IV.

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Endogenous Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Is a Physiological Regulator of Myocardial Oxygen Consumption

Cited by 165 publications

References 45 publications

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

Docking of Endothelial Nitric Oxide Synthase (eNOS) to the Mitochondrial Outer Membrane

Activation of Hsp90/NOS and increased NO generation does not impair mitochondrial respiratory chain by competitive binding at cytochrome C Oxidase in low oxygen concentrations

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