Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction

Tsutsumi, Takayoshi; Ide, Tomomi; Yamato, Masayuki; Kudou, Wataru; Andou, Makoto; Hirooka, Yoshitaka; Utsumi, Hideo; Tsutsui, Hiroyuki; Sunagawa, Kenji

doi:10.1093/cvr/cvm092

Cited by 94 publications

(77 citation statements)

References 34 publications

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“…10). These findings are consistent with the protective effects of ACh on various cardiovascular scathing conditions including HR, myocardial infarction and arrhythmia [22,27,28]. …”

Section: Discussionsupporting

confidence: 87%

Acetylcholine Mediates AMPK-Dependent Autophagic Cytoprotection in H9c2 Cells During Hypoxia/Reoxygenation Injury

Zhao

Sun

et al. 2013

Cell Physiol Biochem

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Background: Acetylcholine (ACh), a neurotransmitter of vagal nerve, offers tolerance to ischemia/reperfusion injury. Given the regulation of autophagy in cardioprotection, this study was to examine the role of autophagy in ACh-elicited protection against hypoxia/reoxygenation (HR) injury. Methods: H9c2 cells were subjected to HR injury. Autophagy was determined by transmission electron microscopy, MDC staining and western blot. MTT kit, LDH and CK release, ATP content and TUNEL assay were used to evaluate cardiomyocytes injury. Atg7 and AMPK knockdown was performed with siRNA transfection. Results: Following 4, 8, 12 and 16 h reoxygenation, autophagosomes were decreased along with reduced cell viability. ACh during 4 h reoxygenation facilitated autophagy as evidence by increased autophagosomes and MDC labeling autophagic vacuoles. H9c2 cells treated with ACh also underwent a biochemical changes by increased ratio of LC3-II/LC3-I and autophagy flux (decreased p62), while muscarinic receptor antagonist atropine suppressed these effects. Induction of autophagy was correlated with enhanced cell survival and decreased apoptosis. Autophagy inhibition with chloroquine and Atg7 siRNA significantly attenuated ACh-induced cytoprotection. ACh-elicited autophagy activation could be related to increased AMPK phosphorylation and decreased mTOR phosphorylation. AMPK siRNA exhibited an elevation in mTOR phosphorylation and reduced the ratio of LC3-II/LC3-I. Importantly, AMPK knockdown desensitized H9c2 cells to ACh-mediated protection. Conclusions: These data provided first evidence that ACh-induced autophagy elicited cytoprotective effects through muscarinic receptor activated-AMPK-mTOR pathway, and suggested a novel mechanism of ACh-induced tolerance against HR injury.

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“…10). These findings are consistent with the protective effects of ACh on various cardiovascular scathing conditions including HR, myocardial infarction and arrhythmia [22,27,28]. …”

Section: Discussionsupporting

confidence: 87%

Acetylcholine Mediates AMPK-Dependent Autophagic Cytoprotection in H9c2 Cells During Hypoxia/Reoxygenation Injury

Zhao

Sun

et al. 2013

Cell Physiol Biochem

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“…Strikingly, Tsutsumi el al . has demonstrated that VNS suppresses ROS overproduction and resets the myocardial redox imbalance [23]. Consistently, our previous studies have shown that ACh, the principle neurotransmitter of vagal nerve, reduces angiotensin II and hypoxia-induced ROS in H9c2 cells [24,25].…”

Section: Introductionsupporting

confidence: 69%

Acetylcholine Promotes ROS Detoxification Against Hypoxia/reoxygenation-Induced Oxidative Stress Through FoxO3a/PGC-1a Dependent Superoxide Dismutase

Sun

Zang

Wang

et al. 2014

Cell Physiol Biochem

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Background/Aims: Acetylcholine (ACh) is known to modulate the cardiac redox environment and thereby suppress reactive oxygen species (ROS) generation during oxidative stress. However, there is little information about its regulation on ROS clearance. Here we investigate the beneficial effects of ACh on superoxide dismutase (SOD) as key ROS-detoxifying enzyme system in cultured rat cardiomyoblasts. Methods: H9c2 cells were subjected to hypoxia/reoxygenation (H/R) to mimic oxidative stress. Western blot was used to detect the expression of SOD and related signaling molecules. Specific protein knockdown was performed with siRNA transfection. Results: ACh treatment on the beginning of reoxygenation decreased ROS and apoptosis. ACh increased ATP synthesis and mitochondrial DNA. Furthermore, ACh significantly reversed H/R-induced reduction in protein expressions and activities of SOD. ACh stimulated peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) and decreased forkhead box subfamily O3a (FoxO3a) phosphorylation. Atropine (muscarinic receptor antagonist) abolished the cytoprotection afforded by ACh. PGC-1α siRNA blocked ACh-induced invigorating effects on SOD2, whereas it did not alter SOD1 and FoxO3a phosphorylation. FoxOSa siRNA drastically decreased the expressions of SOD2 and PGC-1α, while it did not affect SOD1. Conclusion: ACh activates SOD2 within mitochondria through FoxO3a/PGC-1α pathway and up-regulates SOD1 in the cytoplasm, thus protecting against oxidative injury induced by H/R. Our findings provide new insights into mechanisms underlying the cardioprotection of ACh on ROS detoxifying. © 2014 S. Karger AG, Basel

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“…Therefore, we chose 10 -5 mol/L acetylcholine for our experiments, which is consistent with previous studies. 11,45 Overall, our data suggest that acetylcholine prevented H/Rinduced intracellular and mitochondrial Ca 2+ overload and inhibited the apoptotic pathway in endothelial cells, presumably through the M3AChR and PI3K/Akt pathway. Notably, acetylcholine depressed ER-mitochondria interaction at reperfusion by inhibiting VDAC1/Grp75/IP3R1 complex and mitofusin 2 expression, thereby preventing mitochondrial Ca 2+ overload and subsequent cell death ( Figure IX in the onlineonly Data Supplement).…”

Section: Discussionmentioning

confidence: 55%

Reduction of Mitochondria–Endoplasmic Reticulum Interactions by Acetylcholine Protects Human Umbilical Vein Endothelial Cells From Hypoxia/Reoxygenation Injury

et al. 2015

ATVB

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Objective-We explored the role of endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk involving voltage-dependent anion channel-1 (VDAC1)/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 in endothelial cells during hypoxia/reoxygenation (H/R), and investigated the protective effects of acetylcholine. Approach and Results-Acetylcholine treatment during reoxygenation prevented intracellular and mitochondrial Ca 2+ increases and alleviated ER Ca 2+ depletion during H/R in human umbilical vein endothelial cells. Consequently, acetylcholine enhanced mitochondrial membrane potential and inhibited proapoptotic cascades, thereby reducing cell death and preserving endothelial ultrastructure. This effect was likely mediated by the type-3 muscarinic acetylcholine receptor and the phosphatidylinositol 3-kinase/Akt pathway. In addition, interactions among members of the VDAC1/ glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex were increased after H/R and were associated with mitochondrial Ca 2+ overload and cell death. Inhibition of the partner of the Ca 2+ channeling complex (VDAC1 siRNA) or a reduction in ER-mitochondria tethering (mitofusin 2 siRNA) prevented the increased protein interaction within the complex and reduced mitochondrial Ca 2+ accumulation and subsequent endothelial cell death after H/R. Intriguingly, acetylcholine could modulate ER-mitochondria Ca 2+ cross talk by inhibiting the VDAC1/glucoseregulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 expression. Phosphatidylinositol 3-kinase siRNA diminished acetylcholine-mediated inhibition of mitochondrial Ca 2+ overload and VDAC1/glucoseregulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex formation induced by H/R. Conclusions-Our data suggest that ER-mitochondria interplay plays an important role in reperfusion injury in the endothelium and may be a novel molecular target for endothelial protection. Acetylcholine attenuates both intracellular and mitochondrial Ca 2+ overload and protects endothelial cells from H/R injury, presumably by disrupting the ER-mitochondria interaction.

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Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction

Abstract: The present study suggests that VNS modulates the cardiac redox status and adrenergic drive, and thereby suppresses free radical generation in the failing heart.

Cited by 94 publications

References 34 publications

Acetylcholine Mediates AMPK-Dependent Autophagic Cytoprotection in H9c2 Cells During Hypoxia/Reoxygenation Injury

Acetylcholine Mediates AMPK-Dependent Autophagic Cytoprotection in H9c2 Cells During Hypoxia/Reoxygenation Injury

Acetylcholine Promotes ROS Detoxification Against Hypoxia/reoxygenation-Induced Oxidative Stress Through FoxO3a/PGC-1a Dependent Superoxide Dismutase

Reduction of Mitochondria–Endoplasmic Reticulum Interactions by Acetylcholine Protects Human Umbilical Vein Endothelial Cells From Hypoxia/Reoxygenation Injury

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