Ameliorative effect of sevoflurane on endoplasmic reticulum stress mediates cardioprotection against ischemia–reperfusion injury

2019 ◽  
Vol 97 (5) ◽  
pp. 345-351 ◽  
Author(s):  
Ai-Jie Liu ◽  
Chun-Xia Pang ◽  
Guo-Qiang Liu ◽  
Shi-Duan Wang ◽  
Chun-Qin Chu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Initiation Factor ◽  
In Vivo Model ◽  
Akt Inhibitor ◽  
Lactate Dehydrogenase Activity ◽  
Protein Levels

We aimed to investigate whether the cardioprotection of sevoflurane against ischemia–reperfusion (IR) injury is via inhibiting endoplasmic reticulum stress. The rat in vivo model of myocardial IR injury was induced by ligation of the left anterior descending coronary artery. Sevoflurane significantly ameliorated the reduced cardiac function, increased infarct size, and elevated troponin I level and lactate dehydrogenase activity in plasma induced by IR injury. Sevoflurane suppressed the IR-induced myocardial apoptosis. The increased protein levels of glucose-regulated protein 78 and C/EBP homologous protein (CHOP) after myocardial IR were significantly reduced by sevoflurane. The protein levels of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2 (eIF2α), and activating transcription factor 4 (ATF4) were significantly increased in rats with IR and attenuated by sevoflurane treatment. The phosphorylation of Akt was further activated by sevoflurane. The cardioprotection of sevoflurane could be blocked by wortmannin, a PI3K/Akt inhibitor. Our results suggest that the cardioprotection of sevoflurane against IR injury might be mediated by suppressing PERK/eIF2a/ATF4/CHOP signaling via activating the Akt pathway, which helps in understanding the novel mechanism of the cardioprotection of sevoflurane.

scholarly journals New Cardiomyokine Reduces Myocardial Ischemia/Reperfusion Injury by PI3K‐AKT Pathway Via a Putative KDEL‐Receptor Binding

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Leonardo Maciel ◽  
Dahienne Ferreira de Oliveira ◽  
Fernanda Mesquita ◽  
Hercules Antônio da Silva Souza ◽  
Leandro Oliveira ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Receptor Binding ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
In Vivo Model ◽  
Beneficial Effects ◽  
Isolated Hearts ◽  
Infarct Area ◽  
Kdel Receptor

Background CDNF (cerebral dopamine neurotrophic factor) belongs to a new family of neurotrophic factors that exert systemic beneficial effects beyond the brain. Little is known about the role of CDNF in the cardiac context. Herein we investigated the effects of CDNF under endoplasmic reticulum‐stress conditions using cardiomyocytes (humans and mice) and isolated rat hearts, as well as in rats subjected to ischemia/reperfusion (I/R). Methods and Results We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. Recombinant CDNF (exoCDNF) protected human and mouse cardiomyocytes against endoplasmic reticulum stress and restored the calcium transient. In isolated hearts subjected to I/R, exoCDNF avoided mitochondrial impairment and reduced the infarct area to 19% when administered before ischemia and to 25% when administered at the beginning of reperfusion, compared with an infarct area of 42% in the untreated I/R group. This protection was completely abrogated by AKT (protein kinase B) inhibitor. Heptapeptides containing the KDEL sequence, which binds to the KDEL‐R (KDEL receptor), abolished exoCDNF beneficial effects, suggesting the participation of KDEL‐R in this cardioprotection. CDNF administered intraperitoneally to rats decreased the infarct area in an in vivo model of I/R (from an infarct area of ≈44% in the I/R group to an infarct area of ≈27%). Moreover, a shorter version of CDNF, which lacks the last 4 residues (CDNF‐ΔKTEL) and thus allows CDNF binding to KDEL‐R, presented no cardioprotective activity in isolated hearts. Conclusions This is the first study to propose CDNF as a new cardiomyokine that induces cardioprotection via KDEL receptor binding and PI3K/AKT activation.

Abstract 1394: Sublethal Levels of Aldehydes Augmented Cardiac Anti-Oxidant Defense through Activation of eIF2 α -ATF4 Pathway via GCN2 Kinase

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takaharu Katayama ◽  
Motoaki Sano ◽  
Jin Endo ◽  
Kentaro Hayashida ◽  
Tomohiro Matsuhashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Special Importance ◽  
Dependent Manner ◽  
Protein Levels

[Introduction] Despite an increase in the levels of aldehydes, the heart from aldehyde dehydrogenase ( ALDH ) 2*2 -transgenic (Tg) mice, loss of function model of ALDH, exhibited a greater tolerance to oxidative stress via activation of amino acid metabolism leading to glutathione biosynthesis. This study was designed to identify the signaling cascades responsible for the activation of amino acid metabolism by aldehydes. [Methods & Results] (1) Phosphorylation of α -subunit of eukaryotic translation initiation factor 2 (eIF2 α ) and subsequent translational activation of ATF4 have been shown to induce amino acid metabolism as a common response to a wide variety of stressors. Consistent with this, phosphorylation levels of eIF2 α and protein expression of ATF4 were increased in ALDH2*2 -Tg hearts. (2) Among four eIF2 α kinases, general control non-depressible (GCN)2 kinase, a sensor for amino acid insufficiency, was activated in ALDH2*2 -Tg heart. (3) Quantification of intracellular amino acid demonstrated that free histidine concentration in ALDH2*2 -Tg heart was selectively reduced by 50% compared to that in non-Tg littermates. (4) To clarify the functional significance of observed reduction in histidine, ALDH2*2 -Tg mice were fed a high histidine diet. The phosphorylation levels of eIF2 α and the protein levels of ATF4 were diminished by 50% in ALDH2*2 -Tg mice fed the high histidine diet, in agreement with the normalization of histidine concentration. Accordingly, both enhanced tolerance to ischemia-reperfusion injury and elevated levels of glutathione were partially diminished in the heart from ALDH2*2 -Tg mice fed the high histidine diet compared to ALDH2*2 -Tg mice fed normal chow. (5) In culture, exposure to 4-hydroxy-2-nonenal (4-HNE) phosphorylated GCN2 and eIF2 α and increased protein levels of ATF4 in a time-dependent manner. (6) siRNA-mediated knockdown of GCN2 abrogated 4-HNE-induced induction of amino acid metabolic genes. [Conclusions] Activation of eIF2 α -ATF4 pathway via GCN2 kinase might be of special importance in the transcriptional control that coordinately promotes amino acid metabolism in response to aldehydes. Intracellular depletion of free histidine is at least partly involved in the activation of GCN2 kinase by aldehydes.

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