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Protective Actions of H2S in Acute Myocardial Infarction and Heart Failure

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ABSTRACT

Hydrogen sulfide (H2S) was identified as the third gasotransmitter in 1996 following the discoveries of the biological importance of nitric oxide and carbon monoxide. Although H2S has long been considered a highly toxic gas, the discovery of its presence and enzymatic production in mammalian tissues supports a critical role for this physiological signaling molecule. H2S is synthesized endogenously by three enzymes: cystathionine β‐synthase, cystathionine‐γ‐lyase, and 3‐mercaptopyruvate sulfurtransferase. H2S plays a pivotal role in the regulation of cardiovascular function as H2S has been shown to modulate: vasodilation, angiogenesis, inflammation, oxidative stress, and apoptosis. Perturbation of endogenous production of H2S has been associated with many pathological conditions of the cardiovascular system such as diabetes, heart failure, and hypertension. As such, modulation of the endogenous H2S signaling pathway or administration of exogenous H2S has been shown to be cytoprotective. This review article will provide a summary of the current body of evidence on the role of H2S signaling in the setting of myocardial ischemia and heart failure. © 2017 American Physiological Society. Compr Physiol 7:583‐602, 2017.

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Figure 1. Figure 1. Transition of understanding of hydrogen sulfide (H2S) from environmental toxin/poison to mammalian intracellular cell signaling molecule. H2S had been considered exclusively an environmental toxin and poison for centuries. The possibility that H2S is formed naturally and exerts fine control over cellular metabolic processes is a more modern concept introduced only in the past decades. The first step in this transition was in 1989 when H2S was detected in the brain of mammals. In 1996 to 1997, H2S was shown to modulate vascular tone and neuronal function. In 2002, H2S was implicated in vascular function and blood pressure regulation. In 2009, S‐sulfhydration was identified as post‐translational protein modification induced by H2S. In 2013, a clinical trial tested an H2S donor in HF patients.
Figure 2. Figure 2. Endogenous enzymatic synthesis of hydrogen sulfide (H2S). The endogenous production of H2S in mammalian systems has been attributed to three tissue‐specific enzymes: CBS, CSE, and 3‐MST. The substrate for the production of endogenous H2S is L‐cysteine. CBS‐driven H2S production is associated to the condensation of homocysteine with L‐cysteine to yield cystathionine and H2S. CSE converts L‐cysteine into pyruvate, ammonia, and H2S. CAT produces 3‐mercaptopyruvate via driving the reaction of L‐cysteine with α‐ketoglutarate. 3‐mercaptopyruvate is then metabolized by 3‐MST to generate H2S.
Figure 3. Figure 3. Mechanisms of hydrogen sulfide (H2S)‐mediated cardioprotection. H2S targets multiple signaling pathways: activation of ATP‐sensitive potassium channel (KATP), the reperfusion injury salvage kinase pathway, signal transducers and activators of transcription pathway, mitochondrial bioenergetics, VEGF, and nuclear‐factor‐E2‐related factor‐2 (Nrf2) signaling, inhibition of TGF‐β1 and ROS production, and both activation and inhibition of microRNA‐based signal modulation. These signaling changes combine to provide a single cytoprotective effect against myocardial ischemia and HF.
Figure 4. Figure 4. Proposed crosstalk between hydrogen sulfide (H2S), NO, and CO signaling. H2S promotes eNOS activation by inducing phosphorylation of the residue serine 1177. NO enhances CBS and CSE activity leading to an increase of H2S bioavailability. H2S activates heme oxygenase‐1 (OH‐1) enhancing the levels of CO. H2S, NO, and CO synergize their biological effects and exert vascular and cardiac protection.
Figure 5. Figure 5. Endogenous hydrogen sulfide (H2S) regulation of the eNOS during cardiovascular disorders. H2S preserves eNOS function and promotes restoration of NO signaling via activation of VEGF/Akt signaling in the setting of HF. In turn, NO positively modulates the H2S pathway by regulating the expression of H2S‐producing enzymes CBS and CSE.


Figure 1. Transition of understanding of hydrogen sulfide (H2S) from environmental toxin/poison to mammalian intracellular cell signaling molecule. H2S had been considered exclusively an environmental toxin and poison for centuries. The possibility that H2S is formed naturally and exerts fine control over cellular metabolic processes is a more modern concept introduced only in the past decades. The first step in this transition was in 1989 when H2S was detected in the brain of mammals. In 1996 to 1997, H2S was shown to modulate vascular tone and neuronal function. In 2002, H2S was implicated in vascular function and blood pressure regulation. In 2009, S‐sulfhydration was identified as post‐translational protein modification induced by H2S. In 2013, a clinical trial tested an H2S donor in HF patients.


Figure 2. Endogenous enzymatic synthesis of hydrogen sulfide (H2S). The endogenous production of H2S in mammalian systems has been attributed to three tissue‐specific enzymes: CBS, CSE, and 3‐MST. The substrate for the production of endogenous H2S is L‐cysteine. CBS‐driven H2S production is associated to the condensation of homocysteine with L‐cysteine to yield cystathionine and H2S. CSE converts L‐cysteine into pyruvate, ammonia, and H2S. CAT produces 3‐mercaptopyruvate via driving the reaction of L‐cysteine with α‐ketoglutarate. 3‐mercaptopyruvate is then metabolized by 3‐MST to generate H2S.


Figure 3. Mechanisms of hydrogen sulfide (H2S)‐mediated cardioprotection. H2S targets multiple signaling pathways: activation of ATP‐sensitive potassium channel (KATP), the reperfusion injury salvage kinase pathway, signal transducers and activators of transcription pathway, mitochondrial bioenergetics, VEGF, and nuclear‐factor‐E2‐related factor‐2 (Nrf2) signaling, inhibition of TGF‐β1 and ROS production, and both activation and inhibition of microRNA‐based signal modulation. These signaling changes combine to provide a single cytoprotective effect against myocardial ischemia and HF.


Figure 4. Proposed crosstalk between hydrogen sulfide (H2S), NO, and CO signaling. H2S promotes eNOS activation by inducing phosphorylation of the residue serine 1177. NO enhances CBS and CSE activity leading to an increase of H2S bioavailability. H2S activates heme oxygenase‐1 (OH‐1) enhancing the levels of CO. H2S, NO, and CO synergize their biological effects and exert vascular and cardiac protection.


Figure 5. Endogenous hydrogen sulfide (H2S) regulation of the eNOS during cardiovascular disorders. H2S preserves eNOS function and promotes restoration of NO signaling via activation of VEGF/Akt signaling in the setting of HF. In turn, NO positively modulates the H2S pathway by regulating the expression of H2S‐producing enzymes CBS and CSE.
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Erminia Donnarumma, Rishi K. Trivedi, David J. Lefer. Protective Actions of H2S in Acute Myocardial Infarction and Heart Failure. Compr Physiol 2017, 7: 583-602. doi: 10.1002/cphy.c160023