Mitochondria as Targets for Nitric Oxide–Induced Protection During Simulated Ischemia and Reoxygenation in Isolated Neonatal Cardiomyocytes

Rakhit, Roby; Mojet, MH; Marber, Michael; Duchen, Michael R.

doi:10.1161/01.cir.103.21.2617

Cited by 129 publications

(83 citation statements)

References 33 publications

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“…This competition transiently inhibits oxidative phosphorylation, precluding maintenance of ⌬⌿ m in the face of ongoing ATP synthesis. By dissipating ⌬⌿ m during elevations of [Ca 2ϩ ] cytosol , NO may reduce mitochondrial Ca 2ϩ uptake and subsequent cell death in neurons, a phenomenon reported in cardiomyocytes in vitro during ischemia-reperfusion injury (Rakhit et al, 2001). Because NMDA induces mild ⌬⌿ m dissipation in newborn hippocampal neurons with little subsequent death, we hypothesized that this ⌬⌿ m dissipation results from NMDA-induced NO production and that this NO production protects neurons after NMDA.…”

Section: Introductionmentioning

confidence: 93%

Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

Marks¹,

Boriboun²,

Wang³

2005

J. Neurosci.

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Section: Introductionmentioning

confidence: 93%

Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

Marks¹,

Boriboun²,

Wang³

2005

J. Neurosci.

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“…32 NO is known to abolish mitochondrial oxidant damage and calcium overload, and reduce superoxide anion production via an efficient suppression on the activity of NAD(P)H oxidase and the assembly of NAD(P)H oxidase subunits. 1,33 Maintenance of NO levels is critical for recovery of heart failure after ischemic injury. As part of a self-protective process, we found that CHF causes a modest increase in interstitial NO levels (consistent with a previous publication 34 ) and may be derived from activated NOS isoforms and/or a NOS-independent pathway.…”

Section: Cardioprotection By Kallistatin Via Antioxidation L Gao Et Almentioning

confidence: 99%

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Gao

Yin

Smith

et al. 2008

Laboratory Investigation

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Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription-polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-b1 (TGF-b1) and plasminogen activator inhibitor-1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H 2 O 2 , and the antioxidant effect of kallistatin was abolished by No-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H 2 O 2 treatment, and inhibited H 2 O 2 -induced Akt and ERK phosphorylation, as well as NF-kB activation. Furthermore, kallistatin abrogated TGF-b-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action. Myocardial infarction (MI) leads to cardiac remodeling with complex structural alterations. After an ischemic insult, left ventricle (LV) enlargement is followed by progressive diastolic stiffness, enhanced wall stress and oxygen consumption, thus resulting in cardiomyocyte hypertrophy, interstitial fibrosis and decreased cardiac output. Increased reactive oxygen species (ROS) levels are recognized to be involved in ischemic heart failure and considered to be a major cause of cardiomyocyte death, ventricular dysfunction and heart failure progress. 1 Under pathological conditions, increased oxidative stress damages DNA and mitochondrial function, activates proapoptotic signaling kinases and leads to myocyte apoptosis or necrosis. 2,3 Elevation of ROS activates a series of hypertrophic signaling kinases and transcription factors to stimulate cardiac hypertrophy. 3,4 Moreover, ROS stimulate fibroblast proliferation and activate the expression of profibrotic factors, including transforming growth...

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“…An additional limitation is that NO formation from NO synthase requires oxygen as substrate, a molecule whose availability becomes limited during ischemia. We therefore considered the use of nitrite in this context for the following reasons: (a) it is a naturally occurring substance with no potentially toxic "leaving group"; (b) it is selectively reduced to NO in tissues with low oxygen tension and low pH (4, 6-13, 34, 35); and (c) NO is known to maintain heme proteins in a reduced and liganded state (36)(37)(38), to limit free iron-and heme-mediated oxidative chemistry (39)(40)(41), to transiently inhibit cytochrome c oxidase and mitochondrial respiration (42)(43)(44)(45), and to modulate apoptotic effectors (46), all mechanisms that might participate in cytotoxicity after severe ischemia.…”

Section: Introductionmentioning

confidence: 99%

Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver

Duranski¹,

Greer²,

Dejam³

et al. 2005

J. Clin. Invest.

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Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitrosamines, and iron-nitrosylated heme proteins within 1-30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.

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Mitochondria as Targets for Nitric Oxide–Induced Protection During Simulated Ischemia and Reoxygenation in Isolated Neonatal Cardiomyocytes

Abstract: Pretreatment with an NO donor induces a modest, sustained mitochondrial depolarization and protects cardiomyocytes from sI/R injury. The demonstrated reduction in mitochondrial Ca(2+) uptake possibly reduces cytosolic Ca(2+) overload, providing a likely mechanism for NO-induced protection.

Cited by 129 publications

References 33 publications

Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver

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