Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux

Xie, Haiyang; Xu, Qiang; Jia, Jia; Ao, Gui-Zhen; Sun, Ying; Hu, Lifang; Alkayed, Nabil J.; Wang, Chen; Cheng, Jian

doi:10.1016/j.bbrc.2015.02.017

Cited by 81 publications

(57 citation statements)

References 23 publications

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“…7B). Our results agreed with previously published studies as they showed that compound C and 3-MA resulted in cardiac dysfunction by blocking autophagy activation [57]. …”

Section: Discussionsupporting

confidence: 83%

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

Yang

Zhang

Gao

et al. 2017

Cell Physiol Biochem

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Background/Aim: Autophagy plays an important role in cellular homeostasis through the disposal and recycling of cellular components. Hydrogen sulphide (H₂S) is the third endogenous gas that has been shown to confer cardiac protective effects. Given the regulation of autophagy in cardioprotection, this study aimed to investigate the protective effects of H₂S via autophagy during high glucose treatment. Methods: This study investigated the content of H₂S in the plasma as well as myocardial, ultrastructural changes in mitochondria and autophagosomes. This study also investigated the apoptotic rate using Hoechst/PI as well as expression of autophagy-associated proteins and mitochondrial apoptotic proteins in H9C2 cells treated with or without GYY4137. Mitochondria of cardiac tissues were isolated and RCR and ADP/O were also detected. AMPK knockdown was performed with siRNA transfection. Results: In a STZ-induced diabetic model, NaHS treatment not only increased the expression of p-AMPK in diabetic group but further activated cell autophagy. Following 48h high glucose, autophagosomes and cell viability were reduced. The present results showed that autophagy could be induced by H₂S, which was verified by autophagic ultrastructural observation and LC3-I/LC3-II conversion. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. The expressions levels of autophagic-related proteins were significantly elevated. Moreover, H₂S activated the AMPK/rapamycin (mTOR) signalling pathway. Conclusions: Our findings demonstrated that H₂S decreases oxidative stress and protects against mitochondria injury, activates autophagy, and eventually leads to cardiac protection via the AMPK/mTOR pathway.

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“…7B). Our results agreed with previously published studies as they showed that compound C and 3-MA resulted in cardiac dysfunction by blocking autophagy activation [57]. …”

Section: Discussionsupporting

confidence: 83%

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

Yang

Zhang

Gao

et al. 2017

Cell Physiol Biochem

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“…First, the PQC system consists of components other than the proteasome, such as the autophagy machinery and chaperone proteins. H 2 S can protect against myocardial I/R injury by restoring autophagic flux 35 and we have previously reported that Na 2 S increases the expression of heat shock proteins 70 and 90. 7 Either of these mechanisms could contribute to the reduced accumulation of misfolded proteins observed in the Na 2 S-treated heart.…”

Section: Discussionmentioning

confidence: 90%

Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner

Shimizu

Nicholson

Lambert

et al. 2016

Circ: Heart Failure

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Background Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear-factor-E2-related factor-2 (Nrf2) is a cellular target of H2S and facilitator of H2S-mediated cardioprotection following acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure (HF). Methods and Results Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type (WT) littermates were subjected to ischemic-induced HF. WT mice treated with H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left-ventricular function, and less cardiac hypertrophy following the induction of HF. In contrast, Na2S therapy failed to provide protection against HF in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S increased the expression of proteasome subunits, resulting in an increase proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na2S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na2S failed to improve cardiac function when the proteasome was inhibited. Conclusions These findings indicate that Na2S therapy enhances proteasomal activity and function during the development of heart failure in an Nrf2-dependent manner and that this enhancement leads to attenuation in cardiac dysfunction.

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“…138 In relation to cardiopathology, autophagy represents a potentially attractive therapeutic target, particularly in the contexts of ischemic preconditioning 139 and proteostasis. 140 In the experimental setting, it has been possible to identify numerous agents that promote cardiomyocyte autophagy including rapamycin, 141–143 sirtuin activators such as NAD, 144 hydrogen sulfide, 145 various cardioprotective agents (e.g. UTP, diazoxide, and ranolazine), 139 and common clinical therapies such as statins 40 and metformin.…”

Section: Interventional Potentialmentioning

confidence: 99%

“…150 Inhibition of AMP-activated protein kinase (AMPK) with compound C is an indirect means to inhibit autophagy; but its universality remains to be demonstrated. 145 As autophagy is essential for cardiac homeostasis, long-term inhibition is likely to be deleterious. 101 Indeed suppressed cardiomyocyte autophagy results in an increased susceptibility to cardiac damage induced by acute energy stress settings such as fasting or ischemia.…”

Section: Interventional Potentialmentioning

confidence: 99%

Myocardial stress and autophagy: mechanisms and potential therapies

et al. 2017

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Autophagy is a ubiquitous cellular catabolic process responsive to energy stress status. Research over the last decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Autophagy activation has been identified as cardio-protective in some settings (i.e. ischemia and ischemic preconditioning). In other situations chronically elevated levels of autophagy have been linked with cardiopathology (i.e. sustained pressure overload and failure). Autophagy perturbation in diabetic cardiomyopathy is also observed – and has been associated with both adaptive and maladaptive stress responses. Recent findings indicate that various forms of selective autophagy operate in parallel to manage different catabolic ‘cargo’ types including mitochondria, large proteins, glycogen and lipid stores. In this Review, specific circumstances of autophagy induction associated with cardiac benefit or detriment are considered. The various static and dynamic approaches used for measurement of autophagy are critiqued and current inconsistencies in the understanding of autophagy regulation in the heart are highlighted. The future prospects for pharmacological intervention to achieve therapeutic manipulation of autophagic processes are canvassed.

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Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux

Cited by 81 publications

References 23 publications

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner

Myocardial stress and autophagy: mechanisms and potential therapies

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