Life history of eNOS: Partners and pathways

Dudzinski, David M.; Michel, Thomas

doi:10.1016/j.cardiores.2007.03.023

Cited by 348 publications

(357 citation statements)

References 139 publications

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“…5a). Evaluation of phosphorylated eNOS at Ser1177 [21] revealed that diabetes decreases eNOS phosphorylation at Ser1177 in the aorta of non-exercised db/db compared with those of WT mice (Fig. 5b); however, eNOS phosphorylation at Ser1177 was increased with both exercise intensities, with low-intensity exercise demonstrating a greater benefit.…”

Section: Resultsmentioning

confidence: 98%

“…However, some studies suggest a downregulation of eNOS activity during diabetes [37]. Phosphorylation of eNOS is important for post-translational regulation of eNOS activity [21]. The activation of eNOS catalytic function by Ser1177 phosphorylation inhibits the dissociation of calmodulin from eNOS and so increases the rate of eNOS electron transfer to produce NO [21].…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of eNOS is important for post-translational regulation of eNOS activity [21]. The activation of eNOS catalytic function by Ser1177 phosphorylation inhibits the dissociation of calmodulin from eNOS and so increases the rate of eNOS electron transfer to produce NO [21]. In the present study, investigation of eNOS phosphorylation revealed a novel finding, namely that following diabetes Ser1177 phosphorylation was decreased in the aorta of db/db mice, and that an upregulation of phosphorylation levels occurred following exercise, suggesting greater eNOS activity without changes in body weight or glucose related parameters, which correlated well with aorta nitrite levels.…”

Section: Discussionmentioning

confidence: 99%

“…BH 4 can be degraded directly by peroxynitrite [20]. Additionally, BH 4 deficiency and peroxynitrite can uncouple eNOS [21]. Uncoupled eNOS consumes L-Arg to generate more superoxide instead of NO, forming a positive feedback loop and a progressive loss of available NO.…”

Section: Discussionmentioning

confidence: 99%

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Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

et al. 2008

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Aims/hypothesis Exercise ameliorates oxidative stressmediated diabetic vascular endothelial dysfunction through poorly defined mechanisms. We hypothesised that, in addition to improving metabolic parameters, upregulation of antioxidants such as superoxide dismutase (SOD) mediates exercise-induced reductions of oxidative stress and increased nitric oxide (NO) bioavailability, and also restores vasodilatation. Methods Type 2 diabetic db/db and normoglycaemic wildtype mice were exercised at moderate intensity for 1 h a day for 7 weeks, leading to a 10% body weight loss. Sedentary animals or those undergoing a low-intensity exercise regimen causing non-significant weight loss were also used. We examined aortic endothelial cell function, NO bioavailability and various biomarkers of oxidative stress. Results Moderate-intensity exercise lowered body weight, increased mitochondrial manganese SOD (MnSOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also reduced wholebody (plasma 8-isoprostane) and tissue oxidative stress (nitrotyrosine immunostaining or protein carbonyl levels in the aorta). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu/Zn-SOD instead of MnSOD, and still demonstrated all the above benefits in the db/db aorta. Importantly, both exercise protocols improved endothelial-dependent vasodilatation and NO bioavailability without altering hyperglycaemic status in db/db mice. Conclusions/interpretation Exercise reverses diabetic vascular endothelial dysfunction independently of improvements in body weight or hyperglycaemia. Our data suggest that upregulation of eNOS and specific SOD isoforms could play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in type 2 diabetes patients through lifestyle modifications in the management of diabetes.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

et al. 2008

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“…6B). Increased eNOS activity under shear at 21% O 2 compared with shear at lower PO 2 levels may be due to differences in posttranslational protein modifications [nitrosylation, acylation, or phosphorylation of other sites, such as phosphorylation at Ser635 (5,8)] and/or alterations in interactions between eNOS and its regulatory proteins calmodulin, caveolin, HSP90, and platelet EC adhesion molecule-1 (3,22,25,50).…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

Jones¹,

Han²,

Presley³

et al. 2008

American Journal of Physiology-Cell Physiology

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Cultured vascular endothelial cell (EC) exposure to steady laminar shear stress results in peroxynitrite (ONOO Ϫ ) formation intramitochondrially and inactivation of the electron transport chain. We examined whether the "hyperoxic state" of 21% O2, compared with more physiological O2 tensions (PO2), increases the shear-induced nitric oxide (NO) synthesis and mitochondrial superoxide (O2 ⅐ Ϫ ) generation leading to ONOO Ϫ formation and suppression of respiration. Electron paramagnetic resonance oximetry was used to measure O2 consumption rates of bovine aortic ECs sheared (10 dyn/cm 2 , 30 min) at 5%, 10%, or 21% O2 or left static at 5% or 21% O2. Respiration was inhibited to a greater extent when ECs were sheared at 21% O2 than at lower PO2 or left static at different PO2. Flow in the presence of an endothelial NO synthase (eNOS) inhibitor or a ONOO Ϫ scavenger abolished the inhibitory effect. EC transfection with an adenovirus that expresses manganese superoxide dismutase in mitochondria, and not a control virus, blocked the inhibitory effect. Intracellular and mitochondrial O2 ⅐ Ϫ production was higher in ECs sheared at 21% than at 5% O2, as determined by dihydroethidium and MitoSOX red fluorescence, respectively, and the latter was, at least in part, NO-dependent. Accumulation of NO metabolites in media of ECs sheared at 21% O2 was modestly increased compared with ECs sheared at lower PO2, suggesting that eNOS activity may be higher at 21% O2. Hence, the hyperoxia of in vitro EC flow studies, via increased NO and mitochondrial O2 ⅐ Ϫ production, leads to enhanced ONOO Ϫ formation intramitochondrially and suppression of respiration. shear stress; endothelium; mitochondria; reactive oxygen species MITOCHONDRIA ARE THE SUBCELLULAR organelles for the production of cellular energy, but they also activate intracellular signaling pathways that modulate cell proliferation or promote cell cycle arrest and apoptosis by oxidative or nitrosative reactions. These reactions are regulated by the matrix concentration of nitric oxide (NO), which diffuses to the mitochondria from the cytosolic NO synthase (NOS) isoforms and is thought to be produced also locally by a mitochondrial NOS variant (11). In rat heart, skeletal muscle and liver mitochondria (15,57,58), isolated rat hearts (59), and whole animals (68), NO at physiological concentrations binds reversibly and in competition with oxygen (O 2 ) to the reduced binuclear center Cu B /a 3 of cytochrome-c oxidase (complex IV) of the electron transport chain (ETC) and inhibits mitochondrial O 2 uptake. At slightly higher concentrations, NO oxidizes ubiquinol of ubiquinolcytochrome c reductase (complex III) to increase unstable ubisemiquinone, which, by univalent electron transfer to O 2 , produces the reactive O 2 species (ROS) superoxide (O 2 ⅐ Ϫ ) (57, 58). O 2 ⅐ Ϫ generated from that location is released both into the matrix and intermembrane space (51), where it is dismutated to hydrogen peroxide (H 2 O 2 ) by manganese superoxide dismutase (MnSOD) and copper zinc SOD (CuZ...

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Pharmacological Activation of Mitochondrial Biogenesis for the Treatment of Various Pathologies

Gibbs

Scholpa

Beeson

et al. 2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Life history of eNOS: Partners and pathways

Cited by 348 publications

References 139 publications

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

Pharmacological Activation of Mitochondrial Biogenesis for the Treatment of Various Pathologies

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