Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats

2009 ◽  
Vol 234 (5) ◽  
pp. 573-581 ◽  
Author(s):  
Yukichi Murozono ◽  
Naohiko Takahashi ◽  
Tetsuji Shinohara ◽  
Tatsuhiko Ooie ◽  
Yasushi Teshima ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Ischemic Postconditioning ◽  
Initial Moment ◽  
Protective Effects ◽  
Perfused Heart ◽  
Ventricular Performance ◽  
Akt Phosphorylation

We tested the hypothesis that the protective effects of hyperthermia (HT) could be augmented by ischemic postconditioning (PostC) via enhancement of reperfusion-induced Akt phosphorylation. The role of the mitoKATP channel as an effecter to protect hearts against ischemia/reperfusion injury was also investigated. In isolated perfused heart experiments using a Langendorff apparatus, 30 min of no-flow global ischemia was followed by 120 min of reperfusion. Ischemic PostC, 5 cycles of 10-sec reperfusion/10-sec ischemia, was achieved at the initial moment of reperfusion. Hyperthermia (HT, 43°C for 20 min) was applied 24 hr before ischemia onset. Ischemic PostC alone did not show significant protection, but HT did. The HT-induced protection in terms of infarct size, recovery of left ventricular performance, amount of released creatine kinase and apoptosis were enhanced by ischemic PostC. These protective effects were consistent with the levels of Akt phosphorylation 7 min after reperfusion and were completely blocked by the pretreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin. HT-induced protection was also completely abolished by concomitant perfusion with 5-hydroxydecanoate (5HD, 100 μM), an inhibitor of the mitochondrial ATP-sensitive potassium (mitoKATP) channel. However, the potentiated protection by ischemic PostC remained, even in the presence of 5HD. In conclusion, ischemic PostC could potentiate the protective effects of HT possibly via enhancement of reperfusion-induced Akt phosphorylation. Although the opening of the mitoKATP channel is predominantly involved as an effecter in HT-induced protection, potentiated protection by ischemic PostC may involve mechanisms other than the mitoKATP channel.

scholarly journals pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

2015 ◽  
Vol 227 (3) ◽  
pp. 167-178 ◽  
Author(s):  
T Pasqua ◽  
B Tota ◽  
C Penna ◽  
A Corti ◽  
M C Cerra ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Chromogranin A ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Protective Effects ◽  
Perfused Heart ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-serpinin (pGlu-Serp) are positive cardiac β-adrenergic-like modulators, acting through β1-AR/AC/cAMP/PKA pathway. Because in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition, cardioprotection is often blunted because of the limitations on pro-survival Reperfusion Injury Salvage Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, left ventricular developed pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/Akt, MitoKATP channels and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 cells with pGlu-Serp, which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes that can limit infarct size and overcome the hypertension-induced failure of PostC.

Mechanism of decreased adenosine protection in reperfusion injury of aging rats

2000 ◽  
Vol 279 (1) ◽  
pp. H329-H338 ◽  
Author(s):  
Feng Gao ◽  
Theodore A. Christopher ◽  
Bernard L. Lopez ◽  
Eitan Friedman ◽  
Guoping Cai ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Protective Effects ◽  
No Release ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Cardioprotective Effects ◽  
Myocardial Ischemia Reperfusion

The purpose of this study was to determine whether the protective effects of adenosine on myocardial ischemia-reperfusion injury are altered with age, and if so, to clarify the mechanisms that underlie this change related to nitric oxide (NO) derived from the vascular endothelium. Isolated perfused rat hearts were exposed to 30 min of ischemia and 60 min of reperfusion. In the adult hearts, administration of adenosine (5 μmol/l) stimulated NO release (1.06 ± 0.19 nmol · min−1 · g−1, P < 0.01 vs. vehicle), increased coronary flow, improved cardiac functional recovery (left ventricular developed pressure 79 ± 3.8 vs. 57 ± 3.1 mmHg in vehicle, P < 0.001; maximal rate of left ventricular pressure development 2,385 ± 103 vs. 1,780 ± 96 in vehicle, P < 0.001), and reduced myocardial creatine kinase loss (95 ± 3.9 vs. 159 ± 4.6 U/100 mg protein, P < 0.01). In aged hearts, adenosine-stimulated NO release was markedly reduced (+0.42 ± 0.12 nmol · min−1 · g−1 vs. vehicle), and the cardioprotective effects of adenosine were also attenuated. Inhibition of NO production in the adult hearts significantly decreased the cardioprotective effects of adenosine, whereas supplementation of NO in the aged hearts significantly enhanced the cardioprotective effects of adenosine. The results show that the protective effects of adenosine on myocardial ischemia-reperfusion injury are markedly diminished in aged animals, and that the loss in NO release in response to adenosine may be at least partially responsible for this age-related alteration.

scholarly journals Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Rong Chen ◽  
Yun-yan Zhang ◽  
Jia-nan Lan ◽  
Hui-min Liu ◽  
Wei Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intestinal Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Postconditioning ◽  
Intestinal Barrier Function ◽  
Protective Effects ◽  
Nrf2 Pathway ◽  
Intestinal Ischemia Reperfusion

Aims. Ischemic postconditioning (IPO) has a strong protective effect against intestinal ischemia-reperfusion (IIR) injury that is partly related to autophagy. However, the precise mechanisms involved are unknown. Methods. C57BL/6J mice were subjected to unilateral IIR with or without IPO. After 45 min ischemia and 120 min reperfusion, intestinal tissues and blood were collected for examination. HE staining and Chiu’s score were used to evaluate pathologic injury. We test markers of intestinal barrier function and oxidative stress. Finally, we used WB to detect the expression of key proteins of autophagy and the Akt/GSK-3β/Nrf2 pathway. Results. IPO significantly attenuated IIR injury. Expression levels of LC3 II/I, Beclin-1, and p62 were altered during IIR, indicating that IPO enhanced autophagy. IPO also activated Akt, inhibited GSK-3β, induced Nrf2 nuclear translocation, and upregulated HO-1 and NQO1 expression, thus providing protective effects against IIR injury by suppressing oxidative stress. Consistently, the beneficial effects of IPO were abolished by pretreatment with 3-methyladenine, SC66, and brusatol, potent inhibitors of autophagy, Akt, and Nrf2, respectively. Conclusion. Our study indicates that IPO can ameliorate IIR injury by evoking autophagy, activating Akt, inactivating GSK-3β, and activating Nrf2. These findings may provide novel insights for the alleviation of IIR injury.

scholarly journals Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

2019 ◽  
Vol 20 (18) ◽  
pp. 4361 ◽  
Author(s):  
Elena Bresciani ◽  
Laura Rizzi ◽  
Silvia Coco ◽  
Laura Molteni ◽  
Ramona Meanti ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Protective Effects ◽  
Growth Hormone Secretagogues ◽  
Amino Acid Peptide ◽  
Pathological Conditions ◽  
Muscle Impairment

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

scholarly journals Ischemic Postconditioning as a Novel Avenue to Protect against Brain Injury after Stroke

2009 ◽  
Vol 29 (5) ◽  
pp. 873-885 ◽  
Author(s):  
Heng Zhao
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Postconditioning ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Protective Mechanisms ◽  
Mitogen Activated Protein ◽  
Cerebral Ischemic

Ischemic postconditioning initially referred to a stuttering reperfusion performed immediately after reperfusion, for preventing ischemia/reperfusion injury in both myocardial and cerebral infarction. It has evolved into a concept that can be induced by a broad range of stimuli or triggers, and may even be performed as late as 6 h after focal ischemia and 2 days after transient global ischemia. The concept is thought to be derived from ischemic preconditioning or partial/gradual reperfusion, but in fact the first experiment for postconditioning was carried out much earlier than that of preconditioning or partial/gradual reperfusion, in the research on myocardial ischemia. This review first examines the protective effects and parameters of postconditioning in various cerebral ischemic models. Thereafter, it provides insights into the protective mechanisms of postconditioning associated with reperfusion injury and the Akt, mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and ATP-sensitive K+ (KATP) channel cell signaling pathways. Finally, some open issues and future challenges regarding clinical translation of postconditioning are discussed.

Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning

2008 ◽  
Vol 295 (3) ◽  
pp. H1330-H1340 ◽  
Author(s):  
Qian Chen Yong ◽  
Shiau Wei Lee ◽  
Chun Shin Foo ◽  
Kay Li Neo ◽  
Xin Chen ◽  
...  
Keyword(s):  
Hydrogen Sulphide ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Early Period ◽  
Ischemic Postconditioning ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Rat Hearts ◽  
Underlying Mechanisms

The present study aimed to investigate the role of hydrogen sulphide (H2S) in the cardioprotection induced by ischemic postconditioning and to examine the underlying mechanisms. Cardiodynamics and myocardial infarction were measured in isolated rat hearts. Postconditioning with six episodes of 10-s ischemia (IPostC) significantly improved cardiodynamic function, which was attenuated by the blockade of endogenous H2S production with d-l-propargylglycine. Moreover, IPostC significantly stimulated H2S synthesis enzyme activity during the early period of reperfusion. However, d-l-propargylglycine only attenuated the IPostC-induced activation of PKC-α and PKC-ε but not that of PKC-δ, Akt, and endothelial nitric oxide synthase (eNOS). These data suggest that endogenous H2S contributes partially to the cardioprotection of IPostC via stimulating PKC-α and PKC-ε. Postconditioning with six episodes of a 10-s infusion of NaHS (SPostC) or 2 min continuous NaHS infusion (SPostC2) stimulated activities of Akt and PKC, improved the cardiodynamic performances, and reduced myocardial infarct size. The blockade of Akt with LY-294002 (15 μM) or PKC with chelerythrine (10 μM) abolished the cardioprotection induced by H2S postconditioning. SPostC2, but not SPostC, also additionally stimulated eNOS. We conclude that endogenous H2S contributes to IPostC-induced cardioprotection. H2S postconditioning confers the protective effects against ischemia-reperfusion injury through the activation of Akt, PKC, and eNOS pathways.

Protective effect of C5 shRNA on myocardial ischemia–reperfusion injury in rats

2012 ◽  
Vol 90 (10) ◽  
pp. 1394-1402 ◽  
Author(s):  
Kai Tang ◽  
Yunjiu Cheng ◽  
Suhua Wu ◽  
Lijuan Liu ◽  
Lingli Cheng
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion Injury ◽  
Troponin T ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Myocardial Ischemia And Reperfusion ◽  
Akt Phosphorylation

Myocardial ischemia and reperfusion (MI/R) injury is associated with activation of the complement system. Complement activation generates a series of bioactive substances, including early (C3a, C3b) and terminal (C5a, C5b-9) components. The terminal complement components are key mediators of MI/R injury. This study investigated whether C5 shRNA preconditioning has protective effects following MI/R injury and its potential mechanism. Rats were injected with C5 shRNA 2 days before induction of ischemia. The effects of C5 shRNA were evaluated by the assessment of heart function, infarct size, histopathology, inflammatory cytokine levels, and the plasma level of troponin T. Akt phosphorylation was assessed by immunoblotting. C5 shRNA efficiently inhibited C5 expression both in vitro and in vivo, and attenuated MI/R injury. C5 shRNA preconditioning significantly decreased the level of troponin T and the production of pro-inflammatory cytokine. The infarct size was decreased by 40% in C5 shRNA treated rats. Akt phosphorylation increased after C5 shRNA preconditioning. These results suggest that C5 shRNA preconditioning in rats has protective effects following MI/R injury; this may be partly effected by mediating the activation of the PI3K pathway and by phosphorylation of Akt.

Glucocorticoid pretreatment protects cardiac function and induces cardiac heat shock protein 72

2000 ◽  
Vol 279 (2) ◽  
pp. H836-H843 ◽  
Author(s):  
Guro Valen ◽  
Tsutomu Kawakami ◽  
Peeter Tähepôld ◽  
Alexandra Dumitrescu ◽  
Christian Löwbeer ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Posttranscriptional Regulation ◽  
Time Course ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Acute Administration ◽  
Protective Effects ◽  
Heat Shock Protein 72

Acute administration of glucocortiocoids reduces inflammation. Increasing knowledge of the mechanisms of action indicate that pretreatment with glucocorticoids could have organ-protective effects. We investigated whether pretreatment with methylprednisolone (MP) protected the heart against ischemia-reperfusion dysfunction, and we hypothetized that this protection might be due to induction of the cardioprotective heat shock protein 72 (HSP72). Rats were given vehicle or MP-40 mg/kg im as a double injection starting either 24 or 120 h (5 days) before their hearts were excised for Langendorff perfusion ( n = 6–11 hearts in each group). MP improved left ventricular function and coronary flow during reperfusion after 30 min of global ischemia and reduced infarct size. Cardiac HSP72 gradually increased in a 24-h time course after MP treatment, and the increase was sustained 5 days afterward (immunoblotting). HSP72 mRNA was either reduced or unchanged, indicating a posttranscriptional regulation. Pretreatment with hydrocortisone or dexamethasone ( n = 7–8 hearts of each) similarily increased cardiac HSP72 24 h afterward. This paper demonstrates that glucocorticoids increase cardiac HSP72 and protect organ function against ischemia-reperfusion injury.

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