Mitochondrial Mechanisms of Hydrogen Sulfide Induced Suspended Animation

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DESCRIPTION (provided by applicant): The study of natural molecular and cellular adaptations to extreme environmental conditions could result in new therapeutic targets and interventions to treat and prevent numerous human diseases. For example, cardiovascular pathologies resulting from low blood flow and limited O2 supply, such as ischemia/reperfusion damage and stroke, can be studied using animal hibernation models. In hibernating animals, blood flow is globally and reversibly reduced to all organ systems, but ischemia/ reperfusion insults are absent as the reduced vascular supply is matched by global reduction in metabolism. Recent experiments have demonstrated that mammals that do not normally hibernate can be induced to enter a fully reversible hibernation-like state by exposure to air containing low levels of hydrogen sulfide (H2S) in a phenomenon called H2S-induced suspended animation. Rapid induction and controlled reversal of a hibernation-like state in humans would be immediately applicable for critical care, trauma management, organ transplantation, and general surgical procedures. Moreover, H2S, which is known to inhibit mitochondrial respiration, has recently gained recognition as an endogenously produced cell signaling molecule capable of reducing hypertension and cardiovascular disease progression, suggesting therapeutic uses for H2S as well. However, physiological systemic and cellular concentrations of H2S and those that lead to H2S-induced suspended animation are currently unknown, and very little is understood about the altered physiological responses or targeted systemic and mitochondrial responses during H2S-induced suspended animation. With a novel polarographic hydrogen sulfide sensor (PHSS) developed in our laboratory, we make real time H2S measurements under physiological conditions, allowing us to make unique contributions to the understanding of the H2S-induced suspended animation state. In a collaborative effort, we propose to define the H2S-induced suspended animation state and recovery, to characterize blood H2S chemistry, and to investigate mitochondrial responses to H2S. This will allow us to test the mechanistic hypothesis that H2S-induced suspended animation in non-hibernating rodents occurs when inhaled H2S causes an increased concentration of dissolved H2S in whole blood that results in reversible and protected suppression of mitochondrial respiration in tissues. Learning the mechanisms of H2S-induced suspended animation will allow us to test the ability of pharmacologic interventions to mimic conditions of the hibernator in non-hibernating mammalian species. A more detailed investigation and definition of the H2S-induced suspended animation model will uncover novel targets that may improve the morbidity and mortality of numerous patients with acute or even long term cardiovascular pathologies. PUBLIIC HEALTH RELEVANCE: Cardiovascular pathologies resulting from low blood flow and limited oxygen supply, such as ischemia/reperfusion damage and stroke, can be studied using animal hibernation models. Recent experiments have demonstrated that mammals that do not normally hibernate can be induced to enter a fully reversible hibernation-like state by exposure to air containing low levels of hydrogen sulfide (H2S) in a phenomenon called H2S-induced suspended animation. A more detailed definition of the H2S-induced suspended animation model, including physiological responses, blood H2S chemistry and mitochondrial mechanisms, as described in this proposal, will enable this model to be translated to humans as we uncover novel targets that may improve the morbidity and mortality of numerous patients with acute or even long term cardiovascular pathologies.