Oxygen Radical-mediated Reduction in Basal and Agonist-evoked NO Release in Isolated Rat Heart

Paolocci, Nazareno; Biondi, Roberto; Bettini, Marco; Lee, Chang Il; Berlowitz, Carlos O.; Rossi, Ruggero; Xia, Yong; Ambrosio, Giuseppe; LʼAbbate, Antonio; Kass, David A.; Zweíer, Jay L.

doi:10.1006/jmcc.2000.1334

Cited by 99 publications

(66 citation statements)

References 29 publications

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“…The diminished level of superoxide in the reperfused tissue may also attenuate the deleterious peroxynitrite formation and enhance the bioavailability of NO (Paolocci et al, 2001;Khan et al, 2009b) as we have observed in the present study (Fig. 6).…”

Section: Trimetazidine Ameliorates Cardiac Reperfusion Injury 425supporting

confidence: 76%

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Khan¹,

Meduru²,

Mostafa³

et al. 2010

J Pharmacol Exp Ther

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Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (ϪI/R; ϪTMZ), I/R (ϩI/R; ϪTMZ), and TMZ (ϩI/R; ϩTMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 Ϯ 5 versus 84 Ϯ 3% in control), was restored to 72 Ϯ 3% in the TMZ group. Myocardial pO 2 in the TMZ group returned to baseline levels (ϳ20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 Ϯ 3 versus 47 Ϯ 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction.Ischemic heart disease is the leading cause of mortality among both men and women in the United States, and in the world. Clinical interventions such as coronary angioplasty, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty are routinely used to reintroduction of blood flow to an ischemic region of the myocardium. Such interventions are unavoidably accompanied by an enzymatic cascade of reactions that result in damage to the myocardium, termed ischemia/reperfusion (I/R) injury.Although the etiology of I/R injury is intricate, oxidative stress occurs due to an imbalance between free-radical production and the heart's ability to prevent the damage caused by free radicals. Numerous studies have shown that the generation of reactive oxygen species (ROS) in the oxygendeprived tissue plays a crucial role in the cellular oxidative damage that happens during I/R (Zweier et al., 1989;Ambrosio et al., 1993;Griendling and FitzGerald, 2003). The generation of free radicals that occurs during I/R has been reported by several groups (Bolli et al., 1988;Zweier et al., 1989) and has revealed that ROS production peaks within the first few minutes of reperfusion. Free-radical scavengers (e.g., antioxidants) have been shown to protect the heart from oxidative damage resulting from the form...

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Section: Trimetazidine Ameliorates Cardiac Reperfusion Injury 425supporting

confidence: 76%

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Khan¹,

Meduru²,

Mostafa³

et al. 2010

J Pharmacol Exp Ther

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“…In addition to increasing eNOS Thr495 phosphorylation, FK506-mediated activation of PKC␤ II probably leads to increased reactive oxygen species produced by NADPH oxidase. Both FK506 and PKC␤ II have been shown to lead to NADPH oxidase activation, which would increase the oxygen radical-induced decrease in NO bioavailability and result in oxidative stress and endothelial dysfunction (Dekker et al, 2000;Paolocci et al, 2001;Kitada et al, 2003;Khanna and Pieper, 2007;Pandey and Fulton, 2008). Further studies are needed to confirm the role of PKC␤ II in NADPH oxidase activation and whether antioxidant therapy would be effective in restoring endothelial function in FK506-treated patients.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cβ_II-Mediated Phosphorylation of Endothelial Nitric Oxide Synthase Threonine 495 Mediates the Endothelial Dysfunction Induced by FK506 (Tacrolimus)

Chiasson¹,

Quinn²,

Young³

et al. 2011

J Pharmacol Exp Ther

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FK506 [tacrolimus;-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14, 16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxa-azacyclotricosine-1,7,20,21(4H,23H)-tetrone] is used clinically to reduce the incidence of allograft rejection; however, chronic administration leads to endothelial dysfunction and hypertension. We have previously shown that FK506 activates Ca 2ϩ /diacylglycerol-dependent conventional protein kinase C (cPKC), which phosphorylates endothelial nitric oxide synthase (eNOS) at one of its inhibitory sites, Thr495. However, which cPKC isoform is responsible for phosphorylating eNOS Thr495 is unknown. The aim of the current study was to determine the cPKC isoform that is activated by FK506, leading to decreased endothelial function. FK506 reduced endotheliumdependent relaxation responses, yet had no effect on endotheliumindependent relaxation responses in aortas from control mice. Of the various cPKC isoforms, only the administration of a PKC␤ II isoform-specific peptide inhibitor restored aortic relaxation responses to that of controls. In aortic endothelial cells, FK506 significantly increased PKC␤ II activation compared with vehicle-treated controls, and this was prevented by a PKC␤ II isoform-specific peptide inhibitor. In addition, a PKC␤ II isoform-specific peptide inhibitor prevented the increase in eNOS Thr495 phosphorylation induced by FK506. Taken together, our results indicate that ␤ II is the cPKC isoform responsible for phosphorylating eNOS at the inhibitory site Thr495 in response to FK506. PKC␤ II inhibition could prove beneficial in ameliorating the endothelial dysfunction and hypertension in patients treated with FK506.

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“…Aliquots of supernatants were incubated with [ 3 H]arginine (10 mol/L final arginine, 62 Ci/mmol, Amersham) in the presence of 1 mmol/L NADPH, 3 mol/L tetrahydrobiopterin, 600 mol/L CaCl 2 , 1 mol/L flavinadenine dinucleotide, and 1 mol/L flavin mononucleotide in a final volume of 50 L for 60 minutes at room temperature. 24 The reaction was quenched with 400 L of stop buffer (50 mmol/L HEPES and 5 mmol/L EDTA, pH 5.5). Experiments were also performed in the presence of either EGTA (5.0 mmol/L) or N -L-arginine methyl ester (L-NAME) (1 mmol/L).…”

Section: Radioimmunoassay Of Nos Activitymentioning

confidence: 99%

“…Experiments were also performed in the presence of either EGTA (5.0 mmol/L) or N -L-arginine methyl ester (L-NAME) (1 mmol/L). 24 After resin was added, the reaction mixtures were transferred to spin cups and centrifuged.…”

Section: Radioimmunoassay Of Nos Activitymentioning

confidence: 99%

Gene Therapy of Endothelial Nitric Oxide Synthase and Manganese Superoxide Dismutase Restores Delayed Wound Healing in Type 1 Diabetic Mice

et al. 2004

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Background-Nitric oxide (NO) deficiency contributes to diabetic wound healing impairment. The present study tested the hypothesis that increased cutaneous superoxide (O 2 Ϫ ) levels in type 1 diabetic mice cause NO deficiency and delayed wound healing. Methods and Results-Wound healing was markedly delayed in streptozotocin-induced type 1 diabetic mice compared with the normal controls. There were significantly reduced levels of endothelial NO synthase (eNOS) protein and constitutive NOS activity in diabetic wounds, whereas O 2 Ϫ levels were markedly increased. A single regimen of cutaneous gene therapy of eNOS or manganese superoxide dismutase (MnSOD) restored such healing delay, with a concomitant suppression of wound O 2 Ϫ levels and augmentation of both eNOS protein and constitutive NOS activity. Gene therapy of MnSOD also increased cutaneous MnSOD activity. Cutaneous O 2 Ϫ levels were also increased in Ins2Akita diabetic mice. In vitro glucose treatment of cutaneous tissues from normal mice for 24 hours increased O 2

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Oxygen Radical-mediated Reduction in Basal and Agonist-evoked NO Release in Isolated Rat Heart

Cited by 99 publications

References 29 publications

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Protein Kinase Cβ_II-Mediated Phosphorylation of Endothelial Nitric Oxide Synthase Threonine 495 Mediates the Endothelial Dysfunction Induced by FK506 (Tacrolimus)

Gene Therapy of Endothelial Nitric Oxide Synthase and Manganese Superoxide Dismutase Restores Delayed Wound Healing in Type 1 Diabetic Mice

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Oxygen Radical-mediated Reduction in Basal and Agonist-evoked NO Release in Isolated Rat Heart

Cited by 99 publications

References 29 publications

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling

Protein Kinase CβII-Mediated Phosphorylation of Endothelial Nitric Oxide Synthase Threonine 495 Mediates the Endothelial Dysfunction Induced by FK506 (Tacrolimus)

Gene Therapy of Endothelial Nitric Oxide Synthase and Manganese Superoxide Dismutase Restores Delayed Wound Healing in Type 1 Diabetic Mice

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Protein Kinase Cβ_II-Mediated Phosphorylation of Endothelial Nitric Oxide Synthase Threonine 495 Mediates the Endothelial Dysfunction Induced by FK506 (Tacrolimus)