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Involvement of mitochondria in the protective effect of hydrogen sulfide against oxidative stress in cardiomyocytes
S126
Abstracts / Comparative Biochemistry and Physiology, Part A 150 (2008) S124–S129
Ischemic preconditioning (IP) can be obtained with brief periods (few minutes) of myocardial ischemia before an infarcting/index ischemia. IP limits the severity of the injuries brought about by a subsequent ischemia/reperfusion episode. Also postconditioning (PostC), a series of brief (few seconds) reperfusion/ischemia cycles at reperfusion onset, attenuates ischemia/reperfusion injury. We have shown that PostC protection is not dependent on circulating blood factors or cells. In recent years the main idea was that reactive oxygen species (ROS) play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signalling elements of protection in pre-ischemic phase. It has been demonstrated that preconditioning triggering is redox-sensitive, using either ROS scavengers or ROS generators. We have shown that nitroxyl triggers preconditioning via pro-oxidative, and/or nitrosative stress-related mechanism(s). Several metabolites, including acetylcholine, bradykinin, opioids and phenylephrine, trigger preconditioning-like protection via a mitochondrial K ATP-ROS-dependent mechanism. Intriguingly, and in contrast to the above-described theory of ROS as an obligatory part of reperfusion induced damage, some studies suggest the possibility that some ROS species at low concentrations could protect ischemic hearts against reperfusion injury. Yet, we demonstrated that also ischemic PostC is a cardioprotective phenomenon that requires the intervention of redox signalling to be protective. Moreover, very recently it has been shown that redox signalling is also required at the time of myocardial reperfusion to mediate the cardioprotection elicited by preconditioning. Therefore, our and others results suggest that the role of ROS in reperfusion may be reconsidered as they are not only deleterious. doi:10.1016/j.cbpa.2008.04.294
A7.10 Involvement of mitochondria in the protective effect of hydrogen sulfide against oxidative stress in cardiomyocytes D. Mancardi, P. Pagliaro, C. Penna (Università di Torino)
Hydrogen sulfide (H2S) nitric oxide (NO) and carbogen monoxide (CO) have recently been described as endogenous gasotransmitters. Akin NO and CO, H2S plays a role in cellular signaling. We demonstrated that NO and its sibling species HNO can exert preconditioning-like effects in models of ischemia/reperfusion. H2S is constitutively produced by two different enzymes: cystathionin-β-sinthase and cystathionine-γ-lyase with a prevalence in the nervous system and in the cardiovascular system respectively. Although the mechanism of action of H2S has not yet been elucidated, the vasorelaxant effect is mimicked by KATP channel opener and blocked by KATP channels inhibitor (Glibenclamide). Glibenclamide can also partially reduce the negative inotropic effect of H2S in in vivo rat hearts. As we previously showed in an isolated heart model, the cardioprotective effects of NO and HNO can be blocked by mitochondrial KATP channels inhibitors. Evidences have emerged about the cytoprotective effect of H2S in ischemia/reperfusion models and some authors suggest a positive feedback action on NO production through the upregulation of the inducible form of NO sinthase. While H2S cytotoxicity is proved to be mediated by reactive oxygen species formation and mitochondrial depolarization no evidences have so far emerged about the involvement of mitochondria in the prosurvival effect of H2S. We showed that H2S can modulate prosurvival activity of kinases such as ERK, Akt and GSK. It is likely that intracellular concentration of H2S is finely regulated and that its action is bi-modal with deleterious effects for high concentrations and with functional signaling properties at micromolar concentrations.
A7.9 Oxygen sensing or just passing gas: Hydrogen sulfide as the mediator of cardiovascular responses to hypoxia
doi:10.1016/j.cbpa.2008.04.296
K. Olson (Indiana University School of Medicine)
A7.11 The effects of carbon monoxide and hyperbaric oxygen on the cardiovascular system
The ability to “sense” oxygen and couple Po2 to physiological responses is an integral feature of the cardiovascular system and is variously expressed as hypoxic vasodilation (HVD), hypoxic vasoconstriction (HVC), and perhaps myocardial ischemic pre-conditioning (IPC). However, the mechanism(s) whereby tissues sense hypoxia and transduce this into a physiological response remains equivocal. In this talk I will present recent evidence that the metabolism of hydrogen sulfide (H2S) serves as an O2 sensor. In this model the constitutive production of biologically active H2S is offset by mitochondrial oxidation, thereby producing a simple inverse couple between tissue [O2] and [H2S]. This hypothesis is supported by a variety of studies. In blood vessels, hypoxia and H2S produce the same mechanical response (dilation, constriction or multi-phasic), the stimulatory effects of hypoxia and H2S appear to be mutually exclusive, H2S is enzymatically produced by blood vessels and production is inhibited by oxygen, and HVC and HVD are partially or completely blocked by inhibitors of H2S synthesis. In the heart, H2S pre-treatment mimics IPC, myocardial H2S production is inversely coupled to Po2, and purified mitochondria rapidly consume H2S in normoxia. These experiments not only fulfill the criteria that H2S is a biologically relevant gasotransmitter, they also support the hypothesis that H2S metabolism is a physiologically important O2 sensor. Support: NSF Grants IBN 0235223 and IOS 0641436. doi:10.1016/j.cbpa.2008.04.295
R. Handy, A. Moody, J. Yuan (University of Plymouth) Hyperbaric oxygen (HBO) therapy is the administration of 100% oxygen at more than one atmosphere, and is used to successfully treat a variety of clinical conditions such as carbon monoxide (CO) poisoning, and the healing of chronic wounds. The paper reviews the effects of hyperbaric oxygen on the cardiovascular system with particular focus on the heart and angiogenesis in the cardiovascular system. The heart is a target organ for carbon monoxide poisoning, and HBO therapy is regarded as the most effective treatment. However, the heart is also sensitive to hyperoxia and there are concerns that HBO therapy may contribute to oxidative stress in the heart. We have shown that perfusion of the heart with 0.01 or 0.05% CO causes glutathione depletion which can be partly prevented by the addition of antioxidants (Patel et al., 2003, Biochem. Biophys. Res. Comm, 302, 392396), and that CO toxicity is bimodal with the CO:O2 ratio being significant in the toxic mechanism (Patel et al., 2004, Biochem. Biophys. Res. Comm. 321, 241–246). In the vascular system, HBO promotes neoangiogenesis during granulation tissue formation. Angiogenesis is a highly orchestrated event, and the formation of reactive oxidative species (ROS) during HBO has been controversially considered as a regulator for angiogenic factors, as well as a harmful originator for oxidative stress-induced cyto- and genotoxicity in cells. Recent experiments on blood vessels in vitro (Yuan et al., in preparation) show that a single HBO treatment does not induce
Abstracts / Comparative Biochemistry and Physiology, Part A 150 (2008) S124–S129
Ischemic preconditioning (IP) can be obtained with brief periods (few minutes) of myocardial ischemia before an infarcting/index ischemia. IP limits the severity of the injuries brought about by a subsequent ischemia/reperfusion episode. Also postconditioning (PostC), a series of brief (few seconds) reperfusion/ischemia cycles at reperfusion onset, attenuates ischemia/reperfusion injury. We have shown that PostC protection is not dependent on circulating blood factors or cells. In recent years the main idea was that reactive oxygen species (ROS) play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signalling elements of protection in pre-ischemic phase. It has been demonstrated that preconditioning triggering is redox-sensitive, using either ROS scavengers or ROS generators. We have shown that nitroxyl triggers preconditioning via pro-oxidative, and/or nitrosative stress-related mechanism(s). Several metabolites, including acetylcholine, bradykinin, opioids and phenylephrine, trigger preconditioning-like protection via a mitochondrial K ATP-ROS-dependent mechanism. Intriguingly, and in contrast to the above-described theory of ROS as an obligatory part of reperfusion induced damage, some studies suggest the possibility that some ROS species at low concentrations could protect ischemic hearts against reperfusion injury. Yet, we demonstrated that also ischemic PostC is a cardioprotective phenomenon that requires the intervention of redox signalling to be protective. Moreover, very recently it has been shown that redox signalling is also required at the time of myocardial reperfusion to mediate the cardioprotection elicited by preconditioning. Therefore, our and others results suggest that the role of ROS in reperfusion may be reconsidered as they are not only deleterious. doi:10.1016/j.cbpa.2008.04.294
A7.10 Involvement of mitochondria in the protective effect of hydrogen sulfide against oxidative stress in cardiomyocytes D. Mancardi, P. Pagliaro, C. Penna (Università di Torino)
Hydrogen sulfide (H2S) nitric oxide (NO) and carbogen monoxide (CO) have recently been described as endogenous gasotransmitters. Akin NO and CO, H2S plays a role in cellular signaling. We demonstrated that NO and its sibling species HNO can exert preconditioning-like effects in models of ischemia/reperfusion. H2S is constitutively produced by two different enzymes: cystathionin-β-sinthase and cystathionine-γ-lyase with a prevalence in the nervous system and in the cardiovascular system respectively. Although the mechanism of action of H2S has not yet been elucidated, the vasorelaxant effect is mimicked by KATP channel opener and blocked by KATP channels inhibitor (Glibenclamide). Glibenclamide can also partially reduce the negative inotropic effect of H2S in in vivo rat hearts. As we previously showed in an isolated heart model, the cardioprotective effects of NO and HNO can be blocked by mitochondrial KATP channels inhibitors. Evidences have emerged about the cytoprotective effect of H2S in ischemia/reperfusion models and some authors suggest a positive feedback action on NO production through the upregulation of the inducible form of NO sinthase. While H2S cytotoxicity is proved to be mediated by reactive oxygen species formation and mitochondrial depolarization no evidences have so far emerged about the involvement of mitochondria in the prosurvival effect of H2S. We showed that H2S can modulate prosurvival activity of kinases such as ERK, Akt and GSK. It is likely that intracellular concentration of H2S is finely regulated and that its action is bi-modal with deleterious effects for high concentrations and with functional signaling properties at micromolar concentrations.
A7.9 Oxygen sensing or just passing gas: Hydrogen sulfide as the mediator of cardiovascular responses to hypoxia
doi:10.1016/j.cbpa.2008.04.296
K. Olson (Indiana University School of Medicine)
A7.11 The effects of carbon monoxide and hyperbaric oxygen on the cardiovascular system
The ability to “sense” oxygen and couple Po2 to physiological responses is an integral feature of the cardiovascular system and is variously expressed as hypoxic vasodilation (HVD), hypoxic vasoconstriction (HVC), and perhaps myocardial ischemic pre-conditioning (IPC). However, the mechanism(s) whereby tissues sense hypoxia and transduce this into a physiological response remains equivocal. In this talk I will present recent evidence that the metabolism of hydrogen sulfide (H2S) serves as an O2 sensor. In this model the constitutive production of biologically active H2S is offset by mitochondrial oxidation, thereby producing a simple inverse couple between tissue [O2] and [H2S]. This hypothesis is supported by a variety of studies. In blood vessels, hypoxia and H2S produce the same mechanical response (dilation, constriction or multi-phasic), the stimulatory effects of hypoxia and H2S appear to be mutually exclusive, H2S is enzymatically produced by blood vessels and production is inhibited by oxygen, and HVC and HVD are partially or completely blocked by inhibitors of H2S synthesis. In the heart, H2S pre-treatment mimics IPC, myocardial H2S production is inversely coupled to Po2, and purified mitochondria rapidly consume H2S in normoxia. These experiments not only fulfill the criteria that H2S is a biologically relevant gasotransmitter, they also support the hypothesis that H2S metabolism is a physiologically important O2 sensor. Support: NSF Grants IBN 0235223 and IOS 0641436. doi:10.1016/j.cbpa.2008.04.295
R. Handy, A. Moody, J. Yuan (University of Plymouth) Hyperbaric oxygen (HBO) therapy is the administration of 100% oxygen at more than one atmosphere, and is used to successfully treat a variety of clinical conditions such as carbon monoxide (CO) poisoning, and the healing of chronic wounds. The paper reviews the effects of hyperbaric oxygen on the cardiovascular system with particular focus on the heart and angiogenesis in the cardiovascular system. The heart is a target organ for carbon monoxide poisoning, and HBO therapy is regarded as the most effective treatment. However, the heart is also sensitive to hyperoxia and there are concerns that HBO therapy may contribute to oxidative stress in the heart. We have shown that perfusion of the heart with 0.01 or 0.05% CO causes glutathione depletion which can be partly prevented by the addition of antioxidants (Patel et al., 2003, Biochem. Biophys. Res. Comm, 302, 392396), and that CO toxicity is bimodal with the CO:O2 ratio being significant in the toxic mechanism (Patel et al., 2004, Biochem. Biophys. Res. Comm. 321, 241–246). In the vascular system, HBO promotes neoangiogenesis during granulation tissue formation. Angiogenesis is a highly orchestrated event, and the formation of reactive oxidative species (ROS) during HBO has been controversially considered as a regulator for angiogenic factors, as well as a harmful originator for oxidative stress-induced cyto- and genotoxicity in cells. Recent experiments on blood vessels in vitro (Yuan et al., in preparation) show that a single HBO treatment does not induce