Abstract P125: A Novel Role for Survivin in Insulin-induced Inhibition of Myocardial Apoptosis in Ischemic/reperfused Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Rui Si ◽  
Qiujun Yu ◽  
Ning Zhou ◽  
Ling Tao ◽  
Wenyi Guo ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Survivin Expression ◽  
Fold Increase ◽  
Tunel Staining ◽  
Sprague Dawley ◽  
Signaling Mechanism ◽  
Akt Phosphorylation ◽  
Apoptotic Effect

Objectives: Insulin reduces post-ischemic myocardial apoptotic death, but the mechanism remains unclear. Survivin, an anti-apoptotic protein has recently found participating in vascular repair. This study aimed to test the hypothesis that the up-regulation of survivin by insulin may play a role in the antiapoptotic and cardioprotective effects in the ischemic/reperfused (I/R) heart, and further investigate the signaling mechanism involved. Methods : Isolated adult Sprague-Dawley rat hearts were subjected to 30 min regional ischemia and 3 h of reperfusion. The hearts were randomized to receive insulin, insulin plus LY294002 (specific inhibitor of PI3K), or insulin plus rapamycin (specific inhibitor of mTOR) at the start of reperfusion. To further confirm the correlation between survivin and myocardial survival in vitro, cardiomyocytes were infected with adenovirus encoding survivin or transfected with siRNA targeting survivin. Phosphorylation of Akt, mTOR, p70S6K and the expression of protein survivin were determined and infarct size was assessed using TTC staining, cardiomyocytes apoptosis were evaluated after reperfusion by TUNEL staining and DNA laddering. Results: I/R increased myocardial survivin expression. Insulin reperfusion (10 −7 mol/L) resulted in a 4.2-fold increase in survivin expression (P<0.01 vs. I/R alone), which was almost completely blocked by LY294002. Both of the mTOR phosphorylation and survivin expression were inhibited in the group of insulin reperfusion plus LY294002. Rapamycin reperfusion did not change Akt phosphorylation but partially inhibited survivin expression (16.7±1.2 vs. 9.8±1.6, P<0.01 vs. I/R+Ins), which indicated a cardioprotective effect of survivin and a possible PI3K/Akt/mTOR/SVV signaling pathway during I/R. Moreover, over-expressed survivin provides protection against stimulated ischemia reperfusion induced cardiomyocyte apoptosis, while targeting survivin blunted the anti-apoptotic effect of insulin. Conclusion: This study demonstrates that insulin up-regulates myocardial survivin expression, partly at least, via PI3-kinase-mTOR mechanism, which contributes to the anti-apoptotic effect of insulin in the I/R heart.

scholarly journals NLRP3 Inflammasome Activation Attenuates Neuronal Apoptosis by Upregulating Autophagy through AMPK/Beclin-1 Pathway after Intracerebral Hemorrhage with Ventricular Extension in Rats

2021 ◽  
Author(s):  
Zhaoqi Zhang ◽  
Peiwen Guo ◽  
Zhengcai Jia ◽  
Tunan Chen ◽  
Hua Feng
Keyword(s):  
Intracerebral Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Neuronal Apoptosis ◽  
Specific Inhibitor ◽  
Beclin 1 ◽  
Tunel Staining ◽  
Inflammasome Activation ◽  
Sprague Dawley

Abstract BackgroundIn brain, NLRP3 inflammasome, mainly derived from macrophage/microglia, is involved in proinflammatory and neurodeficits after hemorrhage, and autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggested that NLRP3 inflammasome and autophagy played an important role in intracerebral hemorrhage (ICH). Thus, this study was designed to further explore the pathogenesis of neurodeficits after in posthemorrhagic hydrocephalus.MethodsAutologous blood injection model was induced to mimic ICH with ventricular extension (ICH-IVH) in Sprague-Dawley rats. To elucidate the underlying mechanism, the NLRP3 inflammasome inhibitor MCC950 was administered abdominally at 1 h after ICH-IVH. Magnetic resonance imaging, neurobehavioral tests, immunofluorescence, western blotting, Fluoro-Jade C- staining, Tunel staining, and Quantitative RNA Sequencing were performed.ResultsIn the acute phase of ICH-IVH, both the expression of NLRP3 inflammasome and the autophagy of neurons were upregulated. The activated NLRP3 in macrophage/microglia promoted the release of IL-1β to extracellular, which contributed to excessive autophagy, leading to neurons apoptosis both in vivo and in vitro. AMPK/Beclin-1 pathway played an important role in NLRP3-related neurons autophagy. Using MCC950(NLRP3 inflammasome specific inhibitor) treatment after ICH-IVH significantly reduced ventricles dilation, improved neurofunction, down-regulated the release of IL-1β, and alleviated neuroinflammation and excessive autophagy.ConclusionsOur finding demonstrated that NLRP3 inflammasome activated in microglia/macrophage aggravated neurological outcomes and neuronal apoptosis by upregulating autophagy after ICH-IVH, which was partly mediated by the AMPK/Beclin-1 pathway. Therefore, inhibiting the activation of NLRP3 may be a potential therapeutic strategy for the neurodeficits of ICH-IVH patients.

scholarly journals Carbon monoxide protects the kidney through the central circadian clock and CD39

2018 ◽  
Vol 115 (10) ◽  
pp. E2302-E2310 ◽  
Author(s):  
Matheus Correa-Costa ◽  
David Gallo ◽  
Eva Csizmadia ◽  
Edward Gomperts ◽  
Judith-Lisa Lieberum ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Circadian Rhythm ◽  
Organ Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Purinergic Signaling ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Fold Increase ◽  
Signaling Mechanism ◽  
Tissue Recovery

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39−/− and Per2−/− mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

scholarly journals The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1838 ◽  
Author(s):  
Yi Zhang ◽  
Ying Zhang ◽  
Xiao-fei Jin ◽  
Xiao-hong Zhou ◽  
Xian-hui Dong ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Astragaloside Iv ◽  
Ht22 Cells ◽  
Sd Rats ◽  
Neurological Score

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

scholarly journals Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics

2016 ◽  
Vol 310 (10) ◽  
pp. H1360-H1370 ◽  
Author(s):  
Rick J. Alleman ◽  
Alvin M. Tsang ◽  
Terence E. Ryan ◽  
Daniel J. Patteson ◽  
Joseph M. McClung ◽  
...  
Keyword(s):  
Simultaneous Measurement ◽  
Cardiac Electrophysiology ◽  
Ischemia Reperfusion ◽  
Antiarrhythmic Effect ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Isolated Mitochondria ◽  
Reperfusion Arrhythmia ◽  
Exercise Induced

Mitochondria influence cardiac electrophysiology through energy- and redox-sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (ΔΨm) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague-Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of ΔΨm and ECG. After ischemia-reperfusion, the collapse of ΔΨm was commensurate with the onset of arrhythmia. Exercise preserved ΔΨm and decreased the incidence of fibrillation/tachycardia ( P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained ΔΨm during reoxygenation. Finally, we induced anoxia-reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H2O2. Mitochondria from Ex rats sustained respiration with lower rates of H2O2 emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved ΔΨm and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise-induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease.

scholarly journals Phosphorylated AKT preserves stallion sperm viability and motility by inhibiting caspases 3 and 7

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 221-235 ◽  
Author(s):  
Juan M Gallardo Bolaños ◽  
Carolina M Balao da Silva ◽  
Patricia Martín Muñoz ◽  
Antolín Morillo Rodríguez ◽  
María Plaza Dávila ◽  
...  
Keyword(s):  
Critical Role ◽  
Membrane Integrity ◽  
Specific Inhibitor ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Mitochondrial Superoxide ◽  
Phosphorylated Akt ◽  
Sperm Survival

AKT, also referred to as protein kinase B (PKB or RAC), plays a critical role in controlling cell survival and apoptosis. To gain insights into the mechanisms regulating sperm survival after ejaculation, the role of AKT was investigated in stallion spermatozoa using a specific inhibitor and a phosphoflow approach. Stallion spermatozoa were washed and incubated in Biggers–Whitten–Whittingham medium, supplemented with 1% polyvinyl alcohol (PVA) in the presence of 0 (vehicle), 10, 20 or 30 μM SH5, an AKT inhibitor. SH5 treatment reduced the percentage of sperm displaying AKT phosphorylation, with inhibition reaching a maximum after 1 h of incubation. This decrease in phosphorylation was attributable to either dephosphorylation or suppression of the active phosphorylation pathway. Stallion spermatozoa spontaneously dephosphorylated during in vitro incubation, resulting in a lack of a difference in AKT phosphorylation between the SH5-treated sperm and the control after 4 h of incubation. AKT inhibition decreased the proportion of motile spermatozoa (total and progressive) and the sperm velocity. Similarly, AKT inhibition reduced membrane integrity, leading to increased membrane permeability and reduced the mitochondrial membrane potential concomitantly with activation of caspases 3 and 7. However, the percentage of spermatozoa exhibiting oxidative stress, the production of mitochondrial superoxide radicals, DNA oxidation and DNA fragmentation were not affected by AKT inhibition. It is concluded that AKT maintains the membrane integrity of ejaculated stallion spermatozoa, presumably by inhibiting caspases 3 and 7, which prevents the progression of spermatozoa to an incomplete form of apoptosis.Free Spanish abstractA Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/148/2/221/suppl/DC1.

scholarly journals Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1011-1023 ◽  
Author(s):  
Hui Liu ◽  
Xibo Jing ◽  
Aiqiao Dong ◽  
Baobao Bai ◽  
Haiyan Wang
Keyword(s):  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Ros Production ◽  
Rat Cardiomyocytes ◽  
Doxorubicin Treatment ◽  
Myocardial Apoptosis

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

scholarly journals Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

2012 ◽  
Vol 303 (9) ◽  
pp. F1275-F1286 ◽  
Author(s):  
David J. Semple ◽  
Sunil Bhandari ◽  
Anne-Marie L. Seymour
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rate Pressure Product ◽  
Sprague Dawley ◽  
Uremic Cardiomyopathy ◽  
Reperfusion Injury Salvage Kinase ◽  
Cardioprotective Effects ◽  
Kinase Pathway

Chronic kidney disease is associated with a unique cardiomyopathy, characterized by a combination of structural and cellular remodeling, and an enhanced susceptibility to ischemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway due to insulin resistance. The susceptibility of the uremic heart to ischemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Uremia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischemia was investigated in vitro in control and uremic hearts ± insulin ± rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by13C-NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immunoprecipitation. Insulin improved postischemic rate pressure product in control but not uremic hearts, [recovered rate pressure product (%), control 59.6 ± 10.7 vs. 88.9 ± 8.5, P < 0.05; uremic 19.3 ± 4.6 vs. 28.5 ± 10.4, P = ns]. Rosiglitazone resensitized uremic hearts to insulin-mediated cardioprotection [recovered rate pressure product (%) 12.7 ± 7.0 vs. 61.8 ± 15.9, P < 0.05]. Myocardial carbohydrate metabolism remained responsive to insulin in uremic hearts. Uremia was associated with increased phosphorylation of Akt (1.00 ± 0.08 vs. 1.31 ± 0.11, P < 0.05) in normoxia, but no change in postischemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased postischemia in uremic hearts ( P < 0.05). Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uremic hearts post-ischemia-reperfusion and impaired activation of the reperfusion injury salvage kinase pathway may underlie these findings.

scholarly journals miR-19a/b-3p promotes inflammation during cerebral ischemia/reperfusion injury via SIRT1/FoxO3/SPHK1 pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Feng Zhou ◽  
Yu-Kai Wang ◽  
Cheng-Guo Zhang ◽  
Bing-Yi Wu
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Luciferase Assay ◽  
In Vivo Model ◽  
Tunel Staining

Abstract Background Stroke affects 3–4% of adults and kills numerous people each year. Recovering blood flow with minimal reperfusion-induced injury is crucial. However, the mechanisms underlying reperfusion-induced injury, particularly inflammation, are not well understood. Here, we investigated the function of miR-19a/b-3p/SIRT1/FoxO3/SPHK1 axis in ischemia/reperfusion (I/R). Methods MCAO (middle cerebral artery occlusion) reperfusion rat model was used as the in vivo model of I/R. Cultured neuronal cells subjected to OGD/R (oxygen glucose deprivation/reperfusion) were used as the in vitro model of I/R. MTT assay was used to assess cell viability and TUNEL staining was used to measure cell apoptosis. H&E staining was employed to examine cell morphology. qRT-PCR and western blot were performed to determine levels of miR-19a/b-3p, SIRT1, FoxO3, SPHK1, NF-κB p65, and cytokines like TNF-α, IL-6, and IL-1β. EMSA and ChIP were performed to validate the interaction of FoxO3 with SPHK1 promoter. Dual luciferase assay and RIP were used to verify the binding of miR-19a/b-3p with SIRT1 mRNA. Results miR-19a/b-3p, FoxO3, SPHK1, NF-κB p65, and cytokines were elevated while SIRT1 was reduced in brain tissues following MCAO/reperfusion or in cells upon OGD/R. Knockdown of SPHK1 or FoxO3 suppressed I/R-induced inflammation and cell death. Furthermore, knockdown of FoxO3 reversed the effects of SIRT1 knockdown. Inhibition of the miR-19a/b-3p suppressed inflammation and this suppression was blocked by SIRT1 knockdown. FoxO3 bound SPHK1 promoter and activated its transcription. miR-19a/b-3p directly targeted SIRT1 mRNA. Conclusion miR-19a/b-3p promotes inflammatory responses during I/R via targeting SIRT1/FoxO3/SPHK1 axis.

scholarly journals DRD4 Mitigates Myocardial Ischemia/Reperfusion Injury in Association With PI3K/AKT Mediated Glucose Metabolism

2021 ◽  
Vol 11 ◽  
Author(s):  
Xue-song Liu ◽  
Jing Zeng ◽  
Yu-xue Yang ◽  
Chun-lei Qi ◽  
Ting Xiong ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Western Blot ◽  
Troponin T ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Flow Cytometer ◽  
Akt Pathway ◽  
Tunel Staining

Ischemia-reperfusion (I/R) could cause heart irreversible damage, which is tightly combined with glucose metabolism disorder. It is demonstrated that GLUT4 (glucose transporter 4) translocation is critical for glucose metabolism in the cardiomyocytes under I/R injury. Moreover, DRD4 (dopamine receptor D4) modulate glucose metabolism, and protect neurocytes from anoxia/reoxygenation (A/R) injury. Thus, DRD4 might regulate myocardial I/R injury in association with GLUT4-mediated glucose metabolism. However, the effects and mechanisms are largely unknown. In the present study, the effect of DRD4 in heart I/R injury were studied ex vivo and in vitro. For I/R injury ex vivo, DRD4 agonist (PD168077) was perfused by Langendorff system in the isolated rat heart. DRD4 activated by PD168077 improved cardiac function in the I/R-injured heart as determined by the left ventricular developed pressure (LVDP), +dp/dt, and left ventricular end diastolic pressure (LVEDP), and reduced heart damage evidenced by infarct size, the release of troponin T (TNT) and lactate dehydrogenase (LDH). DRD4 activation diminished I/R injury induced apoptosis and enhanced cell viability impaired by I/R injury in cardiomyocyte, showed by TUNEL staining, flow cytometer and CCK8 assay. Furthermore, DRD4 activation did not change total GULT4 protein expression level but increased the membrane GULT4 localization determined by western blot. In terms of mechanism, DRD4 activation increased pPI3K/p-AKT but not the total PI3K/AKT during anoxia/reoxygenation (A/R) injury in vitro. Interestingly, PI3K inhibitor, Wortmannin, blocked PI3K/AKT pathway and depleted the membrane GULT4, and further promoted apoptosis showed by TUNEL staining, flow cytometer, western blot of cleaved caspase 3, BAX and BCL2 expression. Thus, DRD4 activation exerted a protective effect against I/R injury by promoting GLUT4 translocation depended on PI3K/AKT pathway, which enhanced the ability of glucose uptake, and ultimately reduced the apoptosis in cardiomyocytes.

Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia

2002 ◽  
Vol 283 (1) ◽  
pp. H5-H12 ◽  
Author(s):  
Lei Xi ◽  
Demet Tekin ◽  
Erdal Gursoy ◽  
Fadi Salloum ◽  
Joseph E. Levasseur ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Signaling Mechanism ◽  
Late Preconditioning ◽  
Systemic Hypoxia ◽  
Cox 2 ◽  
Oxide Synthase ◽  
Delayed Cardioprotection ◽  
Inducible Nitric Oxide

Chronic systemic hypoxia (SH) enhances myocardial ischemic tolerance in mammals. We studied the delayed cardioprotection caused by acute SH and associated signaling mechanism. Conscious adult male mice were exposed to one or two cycles of hypoxia (H; 10% O2) or normoxia (21% O2) for various durations (30 min, 2 h, 4 h) followed by 24 h of reoxygenation. Hearts were isolated 24 h later and subjected to ischemia-reperfusion in a Langendorff model. Infarct size was reduced in mice pretreated with one (H4h) or two cycles (H4hx2) of 4 h SH compared with normoxia mice ( P < 0.05), which was abolished by an inducible nitric oxide synthase (NOS2) inhibitor ( S-methylisothiourea, 3 mg/kg) given before SH or ischemia. H4hx2 also failed to reduce infarct size in NOS2 knockout mice. Cyclooxygenase-2 (COX-2) inhibitor (NS-398, 10 mg/kg) did not block the protection given either before H4hx2 or ischemia. A two- to three fold increase in myocardial NOS2 expression was observed in H4h, H2hx2, and H4hx2 ( P < 0.05), whereas endothelial NOS (NOS3) or COX-2 remained unchanged. We conclude that acute SH induces delayed cardioprotection, which is triggered and mediated by NOS2, but not by NOS3 or COX-2.

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