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Mildažienė, Vida; Banienė, Rasa; Marcinkeviciute, Ausra; Naučienė, Zita; Kalvėnas, Alvydas; Zimkus, Aurelijus

doi:10.1023/a:1006812128286

Cited by 5 publications

(2 citation statements)

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“…79, 80 Nitroxides such as TEMPO have very low toxicity making them perfect candidates for conjugation with triphenylmethylphosphonium for in vivo use, 81 but antioxidants such as Mito-CP are esters and potentially can be hydrolyzed into inactive 3-carboxyproxyl (CP) 77 and triphenylmethylphosphonium. Furthermore, micromolar concentrations of tetraphenylphosphonium inhibit oxidation of pyruvate, malate, 2-oxoglutarate and glutamate in heart mitochondria, 82 suggesting that triphenylmethylphosphonium conjugates should be used at submicromolar concentrations and tested for side effects on respiration. We have recently described in vivo applications of the mitochondria-targeted SOD mimetic mitoTEMPO, which is resistant to hydrolysis, and low doses of mitoTEMPO (25 nM in vitro and 0.7 mg/kg/day in vivo) did not reveal side effects on respiration.…”

Section: Mitochondria-targeted Antioxidantsmentioning

confidence: 99%

Cross talk between mitochondria and NADPH oxidases

Dikalov

2011

Free Radical Biology and Medicine

703

537

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Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interaction between main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of crosstalk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain condition may stimulate NADPH oxidases. This crosstalk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.

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Section: Mitochondria-targeted Antioxidantsmentioning

confidence: 99%

Cross talk between mitochondria and NADPH oxidases

Dikalov

2011

Free Radical Biology and Medicine

703

537

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“…Nitroxides have very low toxicity and this makes them perfect candidates for conjugation with lipophilic cations (e.g., triphenylmethylphosphonium) for in vivo use [17] . Furthermore, some phosphonium ions may inhibit oxidation of pyruvate, malate, 2-oxoglutarate and glutamate in heart mitochondria at micromolar concentrations [18] suggesting that triphenylmethylphosphonium conjugates should be used at submicromolar concentrations and tested for side effect on respiration. Indeed, low doses of mitoTEMPO did not affect mitochondrial respiration in control cells but improved mitochondrial function in the presence of angiotensin II [6] .…”

Section: Introductionmentioning

confidence: 99%

Antihypertensive effect of mitochondria-targeted proxyl nitroxides

2015

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Superoxide (O2-•) has been implicated in the pathogenesis of many human diseases including hypertension. Mitochondria-targeted superoxide scavenger mitoTEMPO reduces blood pressure; however, the structure–functional relationships in antihypertensive effect of mitochondria-targeted nitroxides remain unclear. The nitroxides are known to undergo bioreduction into hydroxylamine derivatives which reacts with O2-• with much lower rate. The nitroxides of pyrrolidine series (proxyls) are much more resistant to bioreduction compared to TEMPOL derivatives suggesting that mitochondria-targeted proxyls can be effective antioxidants with antihypertensive activity. In this work we have designed and studied two new pyrrolidine mitochondria targeted nitroxides: 3-[2-(triphenyphosphonio)acetamido]- and 3-[2-(triphenyphosphonio) acetamidomethyl]-2,2,5,5-tetramethylpyrrolidine-1-oxyl (mCP2) and (mCP1). These new mitochondria targeted nitroxides have 3- to 7-fold lower rate constants of the reaction with O2-• compared with mitoTEMPO; however, the cellular bioreduction of mCP1 and mCP2 was 3- and 2-fold slower. As a consequence incubation with cells afforded much higher intracellular concentration of mCP1 and mCP2 nitroxides compared to mitoTEMPO nitroxide. This has compensated for the difference in the rate of O2-• scavenging and all nitroxides similarly protected mitochondrial respiration in H2O2 treated endothelial cells. Treatment of hypertensive mice with mCP1 and mCP2 (1.4 mg/kg/day) after onset of angiotensin II-induced hypertension significantly reduced blood pressure to 133±5 mmHg and 129±6 mmHg compared to 163±5 mmHg in mice infused with angiotensin II alone. mCP1 and mCP2 reduced vascular O2-• and prevented decrease of endothelial nitric oxide production. These data indicate that resistance to bioreduction play significant role in antioxidant activity of nitroxides. Studies of nitroxide analogs such as mCP1 and mCP2 may help in optimization of chemical structure of mitochondria-targeted nitroxides for improved efficacy and pharmacokinetics of these drugs in treatment of hypertension and many other conditions including atherosclerosis, diabetes and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role.

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Phenomenological Kinetic and Control Analysis of Oxidative Phosphorylation in Isolated Mitochondria

Borutaitė

Banienė

2011

Mitochondrial Bioenergetics

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Cited by 5 publications

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Cross talk between mitochondria and NADPH oxidases

Cross talk between mitochondria and NADPH oxidases

Antihypertensive effect of mitochondria-targeted proxyl nitroxides

Phenomenological Kinetic and Control Analysis of Oxidative Phosphorylation in Isolated Mitochondria

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