Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion

Comparison of different administration regimens and characterization of the cellular mechanisms of protection

Robert M. Osipov, Michael P. Robich, Jun Feng, Yuhong Liu, Richard T. Clements, Hilary P. Glazer, Neel R. Sodha, Csaba Szabo, Cesario Bianchi, Frank W. Sellke

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Objective: We investigate the impact of different regimens of parenteral hydrogen sulfide (H2S) administration on myocardium during ischemia-reperfusion (IR) and the molecular pathways involved in its cytoprotective effects. Methods: Eighteen male Yorkshire pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either placebo (control, n = 6) or H2S as a bolus (bolus group, n = 6, 0.2 mg/kg over 10 seconds at the start of reperfusion) or as an infusion (infusion group, n = 6, 2 mg•kg•h initiated at the onset of ischemia and continued into the reperfusion period). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis was determined by Monastral blue/triphenyl tetrazolium chloride staining. Apoptosis and the expression pattern of various intracellular effector pathways were investigated in the ischemic territory. Coronary microvascular reactivity to endothelium-dependent and endothelium-independent factors was measured. Results: H2S infusion but not bolus administration markedly reduce myocardial infarct size (P < 0.05) and improve regional left ventricular function, as well as endothelium-dependent and endothelium-independent microvascular reactivity (P < 0.05). The expression of B-cell lymphoma 2 (P = 0.059), heat shock protein 27 and αB-crystallin (P < 0.05) were lower in H2S-treated groups. Infusion of H2S caused higher expression of phospho-glycogen synthase kinase-3 β isoform(P < 0.05) and lower expression of mammalian target of rapamycin and apoptosis-inducing factor (P < 0.05). Bolus of H2S caused higher expression of phospho-p44/42 MAPK extracellular signal-regulated kinase and lower expression of Beclin-1 (P < 0.05). The expression of caspase 3 and cleaved caspase 3 were lower (P < 0.05), whereas the expression of phospho-Bad(Ser136) was higher in the bolus group versus control and infusion groups (P < 0.05). The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell count was lower in both H2S-treated groups compared with the control (P < 0.05). Conclusions: This study demonstrates that infusion of H2S is superior to a bolus alone in reducing myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H2S-treated groups. Thus, the current results indicate that infusion of H2S throughout IR may offer better myocardial protection from IR injury.

Original languageEnglish (US)
Pages (from-to)287-297
Number of pages11
JournalJournal of Cardiovascular Pharmacology
Volume54
Issue number4
DOIs
StatePublished - Oct 2009
Externally publishedYes

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Hydrogen Sulfide
Myocardial Reperfusion
Reperfusion
Myocardial Ischemia
Swine
Endothelium
Ischemia
Reperfusion Injury
Caspase 3
Necrosis
Apoptosis Inducing Factor
HSP27 Heat-Shock Proteins
Apoptosis
Glycogen Synthase Kinase 3
Crystallins
Mitogen-Activated Protein Kinase 3
DNA Nucleotidylexotransferase
Coronary Occlusion
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases

Keywords

  • Apoptosis
  • Cardiac function
  • Heart protection
  • Hydrogen sulfide
  • Microvascular reactivity
  • Myocardial ischemiaâ€"reperfusion injury

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion : Comparison of different administration regimens and characterization of the cellular mechanisms of protection. / Osipov, Robert M.; Robich, Michael P.; Feng, Jun; Liu, Yuhong; Clements, Richard T.; Glazer, Hilary P.; Sodha, Neel R.; Szabo, Csaba; Bianchi, Cesario; Sellke, Frank W.

In: Journal of Cardiovascular Pharmacology, Vol. 54, No. 4, 10.2009, p. 287-297.

Research output: Contribution to journalArticle

Osipov, Robert M. ; Robich, Michael P. ; Feng, Jun ; Liu, Yuhong ; Clements, Richard T. ; Glazer, Hilary P. ; Sodha, Neel R. ; Szabo, Csaba ; Bianchi, Cesario ; Sellke, Frank W. / Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion : Comparison of different administration regimens and characterization of the cellular mechanisms of protection. In: Journal of Cardiovascular Pharmacology. 2009 ; Vol. 54, No. 4. pp. 287-297.
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abstract = "Objective: We investigate the impact of different regimens of parenteral hydrogen sulfide (H2S) administration on myocardium during ischemia-reperfusion (IR) and the molecular pathways involved in its cytoprotective effects. Methods: Eighteen male Yorkshire pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either placebo (control, n = 6) or H2S as a bolus (bolus group, n = 6, 0.2 mg/kg over 10 seconds at the start of reperfusion) or as an infusion (infusion group, n = 6, 2 mg•kg•h initiated at the onset of ischemia and continued into the reperfusion period). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis was determined by Monastral blue/triphenyl tetrazolium chloride staining. Apoptosis and the expression pattern of various intracellular effector pathways were investigated in the ischemic territory. Coronary microvascular reactivity to endothelium-dependent and endothelium-independent factors was measured. Results: H2S infusion but not bolus administration markedly reduce myocardial infarct size (P < 0.05) and improve regional left ventricular function, as well as endothelium-dependent and endothelium-independent microvascular reactivity (P < 0.05). The expression of B-cell lymphoma 2 (P = 0.059), heat shock protein 27 and αB-crystallin (P < 0.05) were lower in H2S-treated groups. Infusion of H2S caused higher expression of phospho-glycogen synthase kinase-3 β isoform(P < 0.05) and lower expression of mammalian target of rapamycin and apoptosis-inducing factor (P < 0.05). Bolus of H2S caused higher expression of phospho-p44/42 MAPK extracellular signal-regulated kinase and lower expression of Beclin-1 (P < 0.05). The expression of caspase 3 and cleaved caspase 3 were lower (P < 0.05), whereas the expression of phospho-Bad(Ser136) was higher in the bolus group versus control and infusion groups (P < 0.05). The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell count was lower in both H2S-treated groups compared with the control (P < 0.05). Conclusions: This study demonstrates that infusion of H2S is superior to a bolus alone in reducing myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H2S-treated groups. Thus, the current results indicate that infusion of H2S throughout IR may offer better myocardial protection from IR injury.",
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T1 - Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion

T2 - Comparison of different administration regimens and characterization of the cellular mechanisms of protection

AU - Osipov, Robert M.

AU - Robich, Michael P.

AU - Feng, Jun

AU - Liu, Yuhong

AU - Clements, Richard T.

AU - Glazer, Hilary P.

AU - Sodha, Neel R.

AU - Szabo, Csaba

AU - Bianchi, Cesario

AU - Sellke, Frank W.

PY - 2009/10

Y1 - 2009/10

N2 - Objective: We investigate the impact of different regimens of parenteral hydrogen sulfide (H2S) administration on myocardium during ischemia-reperfusion (IR) and the molecular pathways involved in its cytoprotective effects. Methods: Eighteen male Yorkshire pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either placebo (control, n = 6) or H2S as a bolus (bolus group, n = 6, 0.2 mg/kg over 10 seconds at the start of reperfusion) or as an infusion (infusion group, n = 6, 2 mg•kg•h initiated at the onset of ischemia and continued into the reperfusion period). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis was determined by Monastral blue/triphenyl tetrazolium chloride staining. Apoptosis and the expression pattern of various intracellular effector pathways were investigated in the ischemic territory. Coronary microvascular reactivity to endothelium-dependent and endothelium-independent factors was measured. Results: H2S infusion but not bolus administration markedly reduce myocardial infarct size (P < 0.05) and improve regional left ventricular function, as well as endothelium-dependent and endothelium-independent microvascular reactivity (P < 0.05). The expression of B-cell lymphoma 2 (P = 0.059), heat shock protein 27 and αB-crystallin (P < 0.05) were lower in H2S-treated groups. Infusion of H2S caused higher expression of phospho-glycogen synthase kinase-3 β isoform(P < 0.05) and lower expression of mammalian target of rapamycin and apoptosis-inducing factor (P < 0.05). Bolus of H2S caused higher expression of phospho-p44/42 MAPK extracellular signal-regulated kinase and lower expression of Beclin-1 (P < 0.05). The expression of caspase 3 and cleaved caspase 3 were lower (P < 0.05), whereas the expression of phospho-Bad(Ser136) was higher in the bolus group versus control and infusion groups (P < 0.05). The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell count was lower in both H2S-treated groups compared with the control (P < 0.05). Conclusions: This study demonstrates that infusion of H2S is superior to a bolus alone in reducing myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H2S-treated groups. Thus, the current results indicate that infusion of H2S throughout IR may offer better myocardial protection from IR injury.

AB - Objective: We investigate the impact of different regimens of parenteral hydrogen sulfide (H2S) administration on myocardium during ischemia-reperfusion (IR) and the molecular pathways involved in its cytoprotective effects. Methods: Eighteen male Yorkshire pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either placebo (control, n = 6) or H2S as a bolus (bolus group, n = 6, 0.2 mg/kg over 10 seconds at the start of reperfusion) or as an infusion (infusion group, n = 6, 2 mg•kg•h initiated at the onset of ischemia and continued into the reperfusion period). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis was determined by Monastral blue/triphenyl tetrazolium chloride staining. Apoptosis and the expression pattern of various intracellular effector pathways were investigated in the ischemic territory. Coronary microvascular reactivity to endothelium-dependent and endothelium-independent factors was measured. Results: H2S infusion but not bolus administration markedly reduce myocardial infarct size (P < 0.05) and improve regional left ventricular function, as well as endothelium-dependent and endothelium-independent microvascular reactivity (P < 0.05). The expression of B-cell lymphoma 2 (P = 0.059), heat shock protein 27 and αB-crystallin (P < 0.05) were lower in H2S-treated groups. Infusion of H2S caused higher expression of phospho-glycogen synthase kinase-3 β isoform(P < 0.05) and lower expression of mammalian target of rapamycin and apoptosis-inducing factor (P < 0.05). Bolus of H2S caused higher expression of phospho-p44/42 MAPK extracellular signal-regulated kinase and lower expression of Beclin-1 (P < 0.05). The expression of caspase 3 and cleaved caspase 3 were lower (P < 0.05), whereas the expression of phospho-Bad(Ser136) was higher in the bolus group versus control and infusion groups (P < 0.05). The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell count was lower in both H2S-treated groups compared with the control (P < 0.05). Conclusions: This study demonstrates that infusion of H2S is superior to a bolus alone in reducing myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H2S-treated groups. Thus, the current results indicate that infusion of H2S throughout IR may offer better myocardial protection from IR injury.

KW - Apoptosis

KW - Cardiac function

KW - Heart protection

KW - Hydrogen sulfide

KW - Microvascular reactivity

KW - Myocardial ischemiaâ€"reperfusion injury

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