Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs

Lavitrano, Marialuisa; Smolenski, Ryszard T.; Musumeci, Antonino; Maccherini, Massimo; Słomińska, Ewa M.; Florio, E. Di; Bracco, Adele; Mancini, Antonio; Stassi, Giorgio; Patti, Mariella; Giovannoni, Roberto; Froio, A; Simeone, F; Forni, Monica; Bacci, Maria Laura; D'Alise, Giuseppe; Cozzi, Emanuele; Otterbein, Leo E.; Yacoub, Magdi H.; Bach, Fritz H.; Calise, Fulvio

doi:10.1096/fj.03-0996fje

Cited by 102 publications

(72 citation statements)

References 20 publications

(24 reference statements)

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“…CORM-3 suppressed sepsis-related increase in NADH/NAD ratio, suggesting a clear improvement of mitochondrial energetics (Lavitrano et al, 2004). Treatment of septic mice with CORM-3 also improved mitochondrial respiration in association with a moderate increase in mitochondrial oxidative stress.…”

Section: Carbon Monoxide Improves Mitochondrial Energetics In Sepsis 645mentioning

confidence: 85%

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

Lancel

Hassoun²,

Favory³

et al. 2009

J Pharmacol Exp Ther

168

135

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Use of metal carbonyl-based compounds capable of releasing carbon monoxide (CO) in biological systems have emerged as a potential adjunctive therapy for sepsis via their antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of mitochondrial dysfunction and biogenesis associated with sepsis has not been investigated. In the present study, we employed a ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac mitochondrial dysfunction and survival in peritonitis-induced sepsis. Peritonitis was performed in mice by cecal ligation and perforation. Tumor necrosis factor-␣, interleukin-10, and nitrite/nitrate plasma levels were tested to evaluate the systemic inflammatory response. Functional mitochondrial studies included determination of membrane potential, respiration, and redox status. Oxidative stress was evaluated by measurements of mitochondrial hydrogen peroxide, carbonyl protein and GSH levels. Mitochondrial biogenesis was assessed by peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ protein expression and mitochondrial DNA (mtDNA) copy number. The systemic inflammatory response elicited by peritonitis was accompanied by mitochondrial energetic metabolism deterioration and reduced PGC-1␣ protein expression. CORM-3 treatment in septic mice restored the deleterious effects of sepsis on mitochondrial membrane potential, respiratory control ratio, and energetics. It is interesting that administration of CORM-3 during sepsis elicited a mild oxidative stress response that stimulated mitochondrial biogenesis with PGC-1␣ protein expression and mtDNA copy number increases. Our results reveal that delivery of controlled amounts of CO dramatically reduced mortality in septic mice, indicating that CO-RMs could be used therapeutically to prevent organ dysfunction and death in sepsis.

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Section: Carbon Monoxide Improves Mitochondrial Energetics In Sepsis 645mentioning

confidence: 85%

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

Lancel

Hassoun²,

Favory³

et al. 2009

J Pharmacol Exp Ther

168

135

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“…Furthermore, bilirubin improved postischemic LV functional recovery in isolated rat hearts subjected to global ischemia (21). The maintenance of adequate coronary perfusion by CO during I/R may help preserve myocardial ATP and creatine phosphate levels to bring about bioenergetic balance in the ischemic myocardium (29). In contrast to these findings, Liu et al (32) showed that CO blunts contractile performance of isolated papillary muscles from rats with cirrhotic cardiomyopathy, suggesting that increased myocardial HO activity may have adverse effects on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction

Liu

Simpson²,

Brunt³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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-We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adenoassociated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 ϫ 10 11 particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure.

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“…To evaluate the effect of GST inhibition on mitochondrial energetics (relative levels of ATP, ADP, and AMP) and redox status (reflected by NAD and NADH ratios) (2,21,31), intracellular adenine nucleotides were extracted from control and experimental cells as described previously (47) and measured by reverse-phase high-performance liquid chromatography (HPLC) and UV detection at 254 nm. Briefly, samples were extracted with ice-cold perchloric acid (0.4 M) and neutralized with equimolar KOH.…”

Section: Methodsmentioning

confidence: 99%

“…KClO 4 was then precipitated by centrifugation, and the supernatant was retained. Levels of ATP, ADP, AMP, NAD ϩ , and ADPR, a breakdown product of NADH following acid precipitation (21,31), were analyzed using the Agilent HPLC 1100 system. The mobile phase was 0.1 M potassium dihydrogen phosphate (pH 6.0) with 0.15 M potassium chloride as phase A and 15% acetonitrile in A as phase B with the Hypersil BDS column and a flow rate 0.9 ml/min.…”

Section: Methodsmentioning

confidence: 99%

Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism

Fletcher

Boshier

Wakabayashi

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism. Am J Physiol Lung Cell Mol Physiol 308: L1274 -L1285, 2015. First published April 10, 2015; doi:10.1152/ajplung.00220.2014.-Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-but not GST-expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD ϩ /NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.N-acetylcysteine; ethacrynic acid; caffeic acid; reactive oxygen species; viability ACUTE LUNG INJURY (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening inflammatory disorders, which may result from both medical and surgical situations such as sepsis, heart surgery, and lung transplantation (41). Among these, ischemia and reperfusion injury constitutes a unique entity, wherein metabolic and oxygen starvation and subsequent reoxygenation can lead to the release and accumulation of reactive oxygen species (ROS) (4). ROS can directly oxidize and damage DNA, protein, and lipid membranes, inactivate antioxidant enzymes, and enhance expression of proinflammatory genes, ultimately leading to cell injury and apoptosis (11).The glutathione-S-transferase (GST) antioxidant enzymes form a multifunctional superfamily of intracellular isozymes that catalyze the conjugation of reduc...

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Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs

Cited by 102 publications

References 20 publications

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction

Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism

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