Ischemic Postconditioning Group Research Articles

Effect of ischaemic postconditioning on markers of myocardial injury in ST-elevation myocardial infarction: a meta-analysis

ObjectivesThis study aimed to perform a meta-analysis of the short-term impact of ischaemic postconditioning (IPoC) on myocardial injury in ST elevation myocardial infarction (STEMI) using surrogate cardiac biomarkers.MethodsEligible studies were...

Effects of ischaemic post-conditioning on eccentric exercise-induced muscle damage.

Exercise-induced muscle damage (EIMD) is a common phenomenon resulting from high-intensity exercise that impairs subsequent performance. Ischaemic post-conditioning (IPOC) is a simple intervention that has been shown to reduce muscle damage after prolonged ischaemia, a condition mechanistically similar to EIMD. The purpose of this study was to determine whether IPOC could alleviate muscle damage after eccentric exercise. Thirty-two young male participants were randomized into either a sham (n = 16) or an IPOC (n = 16) intervention group. Biceps brachii muscle damage was induced by eccentric exercise, with IPOC or sham intervention applied on the dominant arm following exercise (3 cycles of 30 s ischaemia). Visual analogue scale (VAS) pain, arm circumference, muscle thickness, echo-intensity, and microvascular function (using near-infrared spectroscopy) were measured bilaterally at baseline, 24, 48, and 72 hours after eccentric exercise. Biceps curl one repetition maximum (1RM) was also measured. 1RM was higher for the IPOC group at 48 and 72 hours (both p < 0.05). On the dominant arm, VAS pain was lower at 72 hours for the IPOC group (p = 0.039). Muscle thickness was lower at all post-exercise time points for the IPOC group (all p < 0.05). VAS pain, echo-intensity, and arm circumference were elevated on the non-dominant arm in the sham group at 72 hours (all p < 0.05). These parameters all returned to the baseline level for the IPOC group at 72 hours (all p > 0.05IPOC could attenuate the decrease in strength, and alleviate EIMD with both local and remote effects after high-intensity exercise.

Ischemic Postconditioning Confers No Benefit to Left Ventricular Systolic Function: A Meta-Analysis of Cardiac Magnetic Resonance Imaging Results

Ischemic postconditioning (IPoC) is a technique suggested to reduce reperfusion injury in patients suffering acute ST-elevation myocardial infarction (STEMI), although its use is highly controversial. This meta-analysis aimed to evaluate the effect of IPoC with percutaneous coronary intervention in patients with acute STEMI, as measured by follow-up left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging. The investigators searched PubMed, Embase, and Web of Science for all randomized controlled trials published during the last 2 decades. After the removal of duplicates, 2,021 articles from online databases had been identified using relevant search criteria. The included randomized controlled trials had studied patients with acute STEMI and Thrombolysis in Myocardial Infarction flow 0 to 1 at presentation and had measured follow-up LVEF using cardiac magnetic resonance imaging. Overall, 11 studies (n=1,339 patients) qualified for inclusion. In each study, the control group did not differ significantly from the experimental group. The pooled data from included studies were analyzed using standardized mean difference between IPoC and control groups, and the 95% confidence interval for LVEF; the results were visualized using a forest plot. Bivariate regression analyses and 1-way analyses of LVEF coefficient ratios were done to isolate for various clinical and procedural parameters. An analysis of pooled data of the IPoC (n=674) and control (n=665) groups showed that IPoC did not significantly impact follow-up LVEF (using standardized mean difference 0.10, 95% confidence interval 0.00 to 0.21). Further analysis showed that IPoC did not improve follow-up LVEF when isolating for relevant clinical and procedural parameters. In conclusion, the use of IPoC as an adjunctive therapy to percutaneous coronary intervention seemingly provides no benefit to left ventricular systolic function, as quantified with cardiac magnetic resonance imaging, in patients with acute STEMI with Thrombolysis in Myocardial Infarction flow 0 to 1.

Ischemic Postconditioning Attenuates Myocardial Ischemia-Reperfusion-Induced Acute Lung Injury by Regulating Endoplasmic Reticulum Stress-Mediated Apoptosis.

To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells.

Abstract 111: Ischemic Post Conditioning After Asphyxial Arrest In A Diabetic Rat Model

Diabetes (DM) is a pervasive disease associated with increased risk of cardiac arrest (CA) and worse survival. Diabetics display abrogation of post arrest therapies. Ischemic post-conditioning (IPoC) has been shown to improve outcomes in young healthy swine, but never in a DM model. We hypothesized that IPoC would be beneficial for survival of non-DM rats after asphyxial CA and that this benefit would be abrogated in DM. Male Wistar rats were utilized, 12 of 23 underwent induction of DM with injection of streptozotocin (30mg/kg) IP and feeding of western diet for 12 weeks. Rats were intubated, mechanically ventilated, and anesthetized with isoflurane. A non-invasive flow probe was placed on a carotid artery. An internal jugular vein and femoral artery and vein were cannulated. Electrocardiogram, echocardiogram, and arterial blood gas were analyzed. Asphyxial CA, induced by rocuronium and cessation of ventilation, proceeded for 7 min. CPR was initiated utilizing an automated chest compressor at a rate of 200/min. Animals were randomly assigned to standard CPR (S-CPR) or IPoC. IPoC was initiated 40 seconds into CPR with a 20 sec pause followed by 20 sec of compressions, 1 cycle. This cycling was performed 4 total times after which S-CPR was continued. Defibrillation and epinephrine were given, as necessary. Data were collected every 40 sec during CPR and at 15 min, 1 and 2 hr after return of spontaneous circulation (ROSC). Data were analyzed using ANOVA with pairwise comparisons. Significance set at p &lt;.05. Non-DM rats displayed high rates of ROSC in both S-CPR, and IPoC groups, 100% (5 of 5) and 83% (5 of 6) respectively. DM S-CPR rats had a reduced ROSC rate at 14% (1 of 7) which improved to 80% (4 of 5) with IPoC. There were no significant differences between DM S-CPR and IPoC groups during CPR. Only DM rats required defibrillations. DM rats had a significantly longer time to ROSC, higher epinephrine requirement, lower nadir pH, and lower carotid blood flow at end experiment. There was no difference in any marker between non-DM S-CPR and IPoC groups after ROSC. DM was associated with increased injury from CA. IPoC was not harmful to non-DMs but improved ROSC rate and thus survival in DM rats. This is a novel demonstration of IPoC utility in a historically conditioning resistant group.

Postconditioning by Delayed Administration of Ciclosporin A: Implication for Donation after Circulatory Death (DCD).

Heart transplantation is facing a shortage of grafts. Donation after Circulatory Death (DCD) would constitute a new potential of available organs. In the present work, we aimed to evaluate whether Postconditioning (ischemic or with ciclosporin-A (CsA)) could reduce ischemia-reperfusion injury in a cardiac arrest model when applied at the start of reperfusion or after a delay. An isolated rat heart model was used as a model of DCD. Hearts were submitted to a cardiac arrest of 40 min of global warm ischemia (37 °C) followed by 3 h of 4 °C-cold preservation, then 60 min reperfusion. Hearts were randomly allocated into the following groups: control, ischemic postconditioning (POST, consisting of two episodes each of 30 s ischemia and 30 s reperfusion at the onset of reperfusion), and CsA group (CsA was perfused at 250 nM for 10 min at reperfusion). In respective subgroups, POST and CsA were applied after a delay of 3, 10, and 20 min. Necrosis was lower in CsA and POST versus controls (p < 0.01) whereas heart functions were improved (p < 0.01). However, while the POST lost its efficacy if delayed beyond 3 min of reperfusion, CsA treatment surprisingly showed a reduction of necrosis even if applied after a delay of 3 and 10 min of reperfusion (p < 0.01). This cardioprotection by delayed CsA application correlated with better functional recovery and higher mitochondrial respiratory index. Furthermore, calcium overload necessary to induce mitochondrial permeability transition pore (MPTP) opening was similar in all cardioprotection groups, suggesting a crucial role of MPTP in this delayed protection of DCD hearts.

Guanxinning Injection Combined With Ischemic Postconditioning Attenuate Myocardial Ischemic Reperfusion Injury in Chronic Renal Failure Rats by Modulating Mitochondrial Dynamics.

PurposeSalvia miltiorrhiza Bge. (Danshen, DS) and Ligusticum chuanxiong Hort. (Chuanxiong, CX) have been widely used in traditional Chinese medicine to prevent and treat myocardial ischemia and renal insufficiency, and their extracts (Guanxinning injection, GXN) have been reported to exhibit antioxidant, anti-inflammatory, and anti-ischemia-reperfusion injury properties. It is well-established that ischemic postconditioning (IPOC) can protect against myocardial ischemia-reperfusion (I/R) injury in rats with chronic renal failure (CRF). However, little is known on whether GXN combined with IPOC may affect myocardial I/R injury in CRF rats. We sought to observe the effect of GXN combined with IPOC on myocardial I/R injury in CRF rats by quantifying changes in the expression of proteins related to mitochondrial dynamics.Materials and MethodsIn a survey, 90 Wistar rats were randomly divided into 6 groups (15 rats per group): CRF group, I/R group, comorbid group (CRF + I/R), IPOC group, IPOC + GXN group and the sham group. Changes in blood myocardial injury markers, urea, and creatinine were analyzed. Heart tissues were harvested for histomorphometry and western blotting when rats were sacrificed. Myocardial infarction area was measured by Evans blue and Triphenyltetrazolium chloride solution staining. The expressions of mitochondrial fission relative proteins (DRP1 and FIS1) and mitochondrial fusion relative proteins (OPA1 and MFN1) were detected by western blotting.ResultsIPOC could significantly decrease myocardial injury markers and myocardial area of necrosis (AN)/area at risk (AAR) of the comorbid model rats. Further results showed that GXN combined with IPOC could significantly reduce CK-MB levels and myocardial AN/AAR in comorbid model rats compared with the IPOC group. Meanwhile, both IPOC and IPOC + GXN significantly reduced DRP1 levels and increased the MFN1 and OPA1 protein levels in the comorbid model rats. However, compared with the IPOC group, MFN1 and OPA1 protein levels increased significantly in the IPOC + GXN group.ConclusionExtracts of DS and CX combined with IPOC exert a protective effect against myocardial I/R injury in rats with CRF, mediated by increased expression of mitochondrial fusion proteins (MFN1 and OPA1).

The neuroprotective effect and RNA-sequence analysis of postconditioning on the ischemic stroke with diabetes mellitus tree shrew model.

IntroductionPatients with comorbidity of ischemic stroke (IS) and diabetes mellitus (DM) show poor neurological functional recovery, and ischemic postconditioning (IPOC) should be considered a powerful neuroprotective method for IS. However, whether it should be introduced for patients with IS and DM remains controversial. This study established a DM with IS (DMIS) tree shrew model, which was intervened by IPOC to assess its neuroprotective effects and also to analyze the relevant mechanism by RNA‐sequence and bioinformatics analysis.MethodsFifty‐four tree shrews were randomly divided into a sham operation control group, a DMIS group, and an IPOC group (DMIS model), with 18 tree shrews per group. Triphenyl tetrazolium chloride (TTC), hematoxylin‐eosin (HE) staining, transmission electron microscopy (TEM), and RNA‐sequence analysis were performed to assess the IPOC effect.ResultsIPOC reduced infarct size and reduced nerve cell injury in IS tree shrews with DM. RNA‐seq analysis showed that IPOC significantly increased the expression of the homeobox protein SIX3, while downregulating the expression of HLA class II histocompatibility antigens DQ beta 1 chain, CAS1 domain‐containing protein 1, and cytokine receptor‐like factor 2. The most downregulated signaling pathways include the NF‐κB signaling pathway, TNF signaling pathway, and Fc gamma R‐mediated phagocytosis.ConclusionsIPOCs have a neuroprotective effect in a DMIS animal model that reduces infarct size and nerve cell injury. This mechanism might be related to reducing inflammation and stress responses that decreases the activity of TNF and NF‐κB signaling pathways.

Ischemic postconditioning improves the outcome of organs from donors after cardiac death in a pig liver transplantation model and provides synergistic protection with hypothermic machine perfusion.

This study investigated whether ischemic postconditioning (IPO) improved the outcome of organs from donors after cardiac death and had a synergistic effect with hypothermic machine perfusion (HMP) in a pig liver transplantation model. A donor after cardiac death (DCD) model was developed in 48 healthy Bama miniature pigs randomly divided into four groups: simple cold storage group (SCS group), IPO group, HMP group, HMP-IPO group. The levels of serum alanine aminotransferase (ALT), total bilirubin, histopathological findings, apoptotic activity of hepatocytes, international normalized ratio (INR), tumor necrosis factor-α (TNF-α), and Malondialdehyde (MDA) were compared. All recipients in the SCS group died within 6h after transplantation. The livers of the recipients in the IPO had 50% survival on day 5. HMP allowed 83.3% survival and HMP-IPO allowed 100% survival. After reperfusion, the recipients in the IPO and HMP-IPO group had lower ALT and total bilirubin levels, less Suzuki score, less apoptosis, and less injury to hepatocytes and biliary ducts and attenuated inflammatory response and oxidative load. IPO improved the outcome of organs from donors after cardiac death and had a synergistic effect with HMP in the pig liver transplantation model.

Effect of ischemic postconditioning on cell apoptosis and expression of relevant genes in non-culprit coronary arteries

This study was performed to determine the effect of ischemic postconditioning on cell apoptosis and angiotensin II receptor type 1 (AT1), connexin 43 (Cx43), and β-tubulin mRNA expression in non-culprit...

Protective Effects of Ischemic Postconditioning on Livers in Rats with Limb Ischemia-Reperfusion via Glycogen Synthase Kinase 3 beta (GSK-3β)/Fyn/Nuclear Receptor-Erythroid-2-Related Factor (Nrf2) Pathway.

BackgroundIschemia/reperfusion (I/R) injury not only exists in ischemic tissues and organs, but also can cause damage to distant tissues and organs. As the largest metabolic organ of the human body, the liver is very vulnerable to injury after limb I/R. However, the mechanism of liver injury caused by limb I/R injury has not been fully elucidated. This study investigated the effect and mechanism of ischemic postconditioning (IPO) on the liver after hindlimb I/R in rats.Material/MethodsA rat model of hindlimb I/R was established and treated by IPO. Liver function, changes of oxidative stress index and inflammation, Bcl-2 and Bax proteins, and apoptosis were assessed. The structural changes were observed by electron microscopy. GSK-3β/Fyn/Nrf2 levels were detected by quantitative PCR and Western blot.ResultsIPO significantly reduced serum AST, ALP, LDH, and ALT levels induced by I/R. Compared with the I/R group, the levels of SOD, GSH-Px, and CAT in the IPO group were significantly increased, while the levels of MDA, MPO, and ROS were significantly decreased. The IPO group had significantly higher Bcl-2 level and significantly lower Bax level compared to the I/R group. Consistently, IPO decreased the apoptosis rate induced by I/R. Furthermore, IPO lowered the levels of TNF-α, IL-1β, IL-10, and INF-γ and alleviated the ultrastructural changes of hepatocytes. Finally, Nrf2, Fyn, and GSK-3β mRNA and protein levels in the IPO group were significantly higher than in the I/R group.ConclusionsIPO protects against liver injury caused by I/R injury of the hindlimb, possibly via the GSK-3β/Fyn/Nrf2 pathway.

Comparison of infarction size, complete ST-segment resolution incidence, mortality and re-infarction and target vessel revascularization between remote ischemic conditioning and ischemic postconditioning in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

IntroductionDue to higher morbidity and mortality, ST-segment elevation myocardial infarction (STEMI) causes many public health problems.Aim To observe effects of remote ischemic conditioning (RIC) and ischemic postconditioning (IPC) on patients diagnosed as STEMI undergoing primary percutaneous coronary intervention (pPCI).Material and methods This meta-analysis was conducted using indirect comparison by conducting a network meta-analysis (NMA). We conducted searches by utilizing PubMed and the other databases to identify randomized controlled trials (RCTs) that described IPC or RIC treated patients diagnosed with STEMI during processes of pPCI. Enzymatic infarct size and infarction size were evaluated and cardiac events were assessed during the follow-up.ResultsPooled results showed that lower enzymatic infarction size was associated with the RIC group compared to the IPC group (IPC vs. RIC: standardized mean difference (SMD) = 1.126; 95% confidence interval (CI): 0.756–1.677). Compared with IPC, RIC significantly reduced infarction size, which was assessed using cardiac magnetic resonance (CMR) (SMD = 1.113; 95% CI: 0.674–1.837). We noted a potential toward greater complete ST-segment resolution in RIC patients compared with IPC patients (odds ratio (OR) = 0.821; 95% CI: 0.166–4.051). No significant difference existed in all-cause mortality (OR = 2.211; 95% CI: 0.845–5.784), Target vessel revascularization (TVR) (OR = 0.045; 95% CI: 0.001–.662) or re-infarction (OR = 1.763; 95% CI: 0.741–4.193).ConclusionsThis meta-analysis suggested RIC was correlated with significantly smaller infarction size compared to IPC. No significant superiority between RIC and IPC has been observed in this study on cSTR incidence, mortality and re-infarction or TVR.

Effects of Ischemic Post-Conditioning on the Expressions of LC3-II and Beclin-1 in the Hippocampus of Rats After Cerebral Ischemia and Reperfusion.

ObjectiveTo investigate the effects of postconditioning ischemia on the expressions of the hippocampus neuron autophagy-related proteins LC3-II and Beclin-1 in rats following cerebral ischemia reperfusion.MethodsA total of 128 male Sprague–Dawley rats were randomly divided into 4 groups: control, cerebral ischemia-reperfusion (IR), cerebral ischemia post-conditioning group (IP), and PI3K/Akt inhibitor (LY294002). The rat cerebral ischemia model was established by the improved Pulsinelli four vessel occlusion method. The durations across the platform and escape latent period were recorded using the water maze experiment. The changes in cell morphology and the number of surviving hippocampal neurons were detected by hematoxylin-eosin (HE) staining. The cells with Beclin-1 and LC3-II in the hippocampal region were detected by immunohistochemical staining and Western blotting.ResultsWhen compared with the IR at 48 and 72 h, the number of platform passes increased and the escape latency time was shortened. Consequently, the HE staining detected positive cells with LC3-II and Beclin-1 increased in number at each time point in immunohistochemistry and the expressions of the LC3-II and Beclin-1 proteins were improved in the IP (P < 0.05).ConclusionsCerebral ischemic post-conditioning promoted the expressions of autophagy-related proteins LC3-II and Beclin-1 while relieving the injuries caused by cerebral ischemia reperfusion.

Ischemic postconditioning lightening ischemia/reperfusion apoptosis of rats via mitochondria pathway.

To explore whether ischemic postconditioning will lighten hepatic apoptosis caused by hepatic ischemia/reperfusion injury by inhibiting the mitochondria pathway. Pathomorphology of hepatic tissues in rats was observed under an optical microscope after hematoxylin-eosin (HE) staining. Hepatic apoptosis was detected using agarose gel electrophoresis (AGE) with DNA fragments and flow cytometry. Changes in morphology structure of mitochondria in hepatocytes of rats were observed under an electron microscope. Changes in mitochondria transmembrane potential of hepatocytes of rats were detected using a laser scanning confocal microscope (LSCM). Western blotting was adopted to detect changes in the expression of caspase-3 and cytochrome C protein in hepatocytes of rats. Compared with that in I/R group, swelling degree of mitochondria in most hepatocytes of rats in ischemic postconditioning (IPOST) group and IPC group was lighter. Changes in expression of caspase-3 and cytochrome C protein in hepatic cells of rats: caspase-3 was lowly expressed and cytochrome C was highly expressed in S group. The expression of caspase-3 was evidently higher in I/R group than that in S group and expression of cytochrome C protein was evidently lower than that in S group (p<0.05). The expression of caspase-3 protein was evidently decreased in IPOST group and IPC group and the expression of cytochrome C protein was evidently increased (p<0.05). IPOST can reduce hepatic apoptosis caused by hepatic ischemia/reperfusion injury in rats, which may be achieved by inhibiting the mitochondria pathway.

Inhibition of glycogen synthase kinase-3β is involved in cardioprotection by α7nAChR agonist and limb remote ischemic postconditionings.

The present study was designed to determine whether glycogen synthase kinase-3β (GSK-3β) was involved in the cardioprotection by α7 nicotinic acetylcholine receptor (α7nAChR) agonist and limb remote ischemic postconditionings. Forty male Sprague-Dawley rats were randomly divided equally into control (C), α7nAChR agonist postconditioning (P), limb remote ischemic postconditioning (L), combined α7nAChR agonist and limb remote ischemic postconditioning (P+L) groups. At the end of experiment, serum cTnI, creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high mobility group protein (HMGB1) and interleukin-10 (IL-10) levels were measured; infarct size (IS), myocardial expressions of GSK-3β, p-GSK-3β (Ser9), nuclear factor-κB (NF-κB) and p-NF-κB (Ser536) in the ischemic area were assessed. The results showed that compared with group C, IS, serum cTnI and CK-MB levels obviously decreased in groups P, L and P+L. Compared with groups P and L, IS, serum cTnI and CK-MB levels significantly decreased in group P+L. Compared with group C, serum TNF-α, IL-6 and HMGB1 levels, and myocardial expression of p-NF-κBp65 (Ser536) evidently decreased, and myocardial expression of p-GSK-3β (Ser9) obviously increased in groups P, L and P+L. Compared with group P, serum TNF-α, IL-6 and HMGB1 levels and myocardial expression of p-NF-κBp65 (Ser536) significantly increased, and myocardial expression of p-GSK-3β (Ser9) evidently decreased in group L. Compared with group L, serum TNF-α, IL-6, HMGB1 levels, and myocardial expression of p-NF-κBp65 (Ser536) significantly decreased, and myocardial expression of p-GSK-3β (Ser9) obviously increased in group P+L. In conclusion, our findings indicate that inhibition of GSK-3β to decrease NF-κB transcription is one of cardioprotective mechanisms of α7nAChR agonist and limb remote ischemic postconditionings by anti-inflammation, but improved cardioprotection by combined two interventions is not completely attributable to an enhanced anti-inflammatory mechanism.

The involvement of p38MAPK in the rat model of lower-extremity arterial ischemia-reperfusion injury.

This study aims to investigate the regulatory role of p38 mitogen-activated protein kinase (p38MAPK) in rats with lower-extremity arterial ischemia-reperfusion injury. A total of 60 Sprague-Dawley (SD) rats were randomly divided into four groups: control group (Group A), lower-extremity arterial ischemia-reperfusion group (Group B), lower-extremity arterial ischemic postconditioning group (Group C), and lower-extremity arterial ischemic postconditioning + SB203580 group (Group D, 5 μmol/L SB203580, the inhibitor of MAPK pathway, was injected after lower-extremity arterial ischemic postconditioning). The lower-extremity arterial vessels were collected after 24 h. The apoptosis in the lower-extremity arterial vessel in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. The expression of phosphorylated (p)-p38MAPK was measured via Western blotting, and the level of p-activating transcription factor-2 (ATF-2) was detected via immunohistochemical method. The positive rate of apoptotic cells (%) in Group B was significantly increased compared to that in Group A (p<0.05). However, the positive rate was statistically decreased by postcondition in Group C, the rate was further reduced after injection of SB203580 in Group D compared to Group B (p<0.05). Compared with that in Group C, the expressions of p-p38MAPK and p-ATF-2 in Group D were significantly downregulated after injection of SB203580 (p<0.05). Lower-extremity arterial ischemia-reperfusion postconditioning can significantly reduce the apoptosis level in vascular tissues, decrease the expressions of p-p38MAPK and downstream factor ATF-2, and alleviate the damage in lower-extremity arterial vessels. The inhibition of MAPK pathway further restricted the apoptosis and contributed to a promoting role in the recovery of lower-extremity arterial ischemia-reperfusion injury.

Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway

BackgroundThe protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP).MethodsWe used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 μg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis.ResultsWe found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1.ConclusionIn conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.

Effect of inhibition of P38MAPK phosphorylation on learning and memory and autophagy in hippocampus of rats after cerebral ischemic postconditioning

Objective To investigate the effect of ischemic postconditioning on autophagy and learning and memory impairment in rats with ischemia-reperfusion injury by P38MAPK. Methods Ninty-six rats were randomly divided into sham group (Sham group), cerebral ischemia reperfusion group (CIR group), cerebral ischemic postconditioning group (CIP group) and cerebral ischemic postconditioning combined with SB203580 group (CIP + SB203580 group), and 24 rats in each group. The rat model of cerebral ischemia was established by Pulsinelli four-vessel occlusion. The learning and memory abilities of rats were measured by Morris water maze. HE staining were used to detect the morphological changes of hippocampal neurons. The phosphorylation of P38MAPK and Beclin-1, LC3-Ⅱexpression were observed by immunohistochemistry. Results Compared with the Sham group, the number of crossing the platform decreased(24 h: (3.04±0.20)times), and the escape latency was longer in CIR group(24 h: (58.38±1.52) s) (all P<0.05). The number of survival neurons reduced (24 h: 70.93±1.86), and the expression of P38MAPK, LC3-II, Beclin-1 in immunohistochemistry were increased in CIR group(all P<0.05). Compared with CIR group, the number of crossing the platform at each time point increased (24 h: (5.46±0.50)times), the escape latency was shorter (24 h: (52.42±1.53)s), the number of survival neurons increased at each time point(24 h: (83.07±5.30)) and the expression level of P38MAPK decreased in the CIP group, while the expression level of LC3-II, Beclin-1 increased (all P<0.05). Compared with the CIP group, the number of crossing the platform((24 h: (7.13±0.33)times), the escape latency was shorter (24 h: (48.04±1.39)s), the number of survival neurons increased at each time point(24 h: (91.40±1.74)), and the expression of P38MAPK was down-regulated, while the expression of LC3-II, Beclin-1 were up-regulated in CIP + SB203580 group(all P<0.05). Conclusion Ischemic postconditioning can improve learning and memory impairment in rats with ischemia-reperfusion injury by P38MAPK regulating autophagy. Key words: P38MAPK; Ischemic postconditioning; Learning and memory; Autophagy; Rat

Mechanism underlying inhibition of inflammatory responses induced by α7nAChR agonist postconditioning alone or in combination with remote limb ischemic postconditioning during myocardial I/R in rats: the relationship with GSK-3β

Objective To evaluate the relationship between the mechanism underlying inhibition of inflammatory responses induced by α7 nicotinic acetylcholine receptor(α7nAChR)agonist postconditioning alone or in combination with remote limb ischemic postconditioning during myocardial ischemia-reperfusion(I/R)and glycogen synthase kinase-3β(GSK-3β)in rats. Methods Eighty adult male Sprague-Dawley rats, aged 8 weeks, weighing 290-320 g, were divided into 4 groups(n=20 each)using a random number table: I/R group, α7nAChR agonist postconditioning group(group P), remote limb ischemic postconditioning group(group L)and α7nAChR agonist postconditioning plus remote limb ischemic postconditioning group(group P+ L). Myocardial I/R was induced by 30 min occlusion of the left anterior descending branch of coronary artery followed by 120 min reperfusion.Specific α7nAChR agonist PNU282987 2 mg/kg was intravenously injected immediately before reperfusion in group P. In group L, limb ischemia was induced by tourniquet occlusion of bilateral hind paws for 10 min starting from 20 min of myocardial ischemia, and the tourniquet was released at the beginning of reperfusion.Combination of intervention measures previously described in P and L groups was performed in group P+ L.Venous blood samples were taken at 120 min of reperfusion for determination of serum troponin I(TnI)and creatine kinase-MB(CK-MB)concentrations, myocardial infarct size(IS)and expression of phosphorylated GSK-3β [p-GSK-3β(Ser536)], NF-κBp65 and phosphorylated nuclear factor-κBp65(p-NF-κBp65)in myocardial tissues(by Western blot). Results Compared with group I/R, myocardial IS and serum cTnI and CK-MB concentrations were significantly decreased, the expression of p-GSK-3β(Ser9)in ischemic area was up-regulated, and the expression of p-NF-κBp65 in ischemic area was down-regulated in P, L and P+ L groups(P<0.05). Compared with group L, myocardial IS and serum cTnI and CK-MB concentrations were significantly decreased, the expression of p-GSK-3β(Ser9)in ischemic area was up-regulated, and the expression of p-NF-κBp65 in ischemic area was down-regulated in group P+ L(P<0.05). Conclusion The mechanism by which α7nAChR agonist postconditioning alone or in combination with remote limb ischemic postconditioning inhibits inflammatory responses during myocardial I/R may be related to inhibiting GSK-3β activity in rats. Key words: Myocardial reperfusion injury; Inflammation; Glycogen synthase kinase 3; Cholinergic agonists; Extremities; Ischemic postconditioning

Remote Ischemic Postconditioning Protects against Myocardial Ischemia-Reperfusion Injury by Inhibition of the RAGE-HMGB1 Pathway.

Background The aim of the present study was to observe the effect of RAGE-HMGB1 signal pathway on remote ischemic postconditioning in mice with myocardial ischemia reperfusion injury. Methods Mice model of MIRI was established and randomly divided into three groups: control group, ischemia reperfusion group, and remote ischemic postconditioning group. Infarction size was detected by Evans blue and TTC staining. Cardiac function was detected by echocardiography measurement. The protein levels of RAGE, HMGB1, P-AKT, and ERK1/2 were detected by Western blot 120 min following reperfusion. Results RIPostC could decrease the infarct size and increase LVEF and FS compared with I/R group. Two hours after myocardial ischemia reperfusion, the levels of RAGE and HMGB1 were significantly decreased in RIPostC group compared with those in I/R group. The level of p-AKT was significantly higher in the RIPostC group than in the I/R group. LY294002 significantly attenuated RIPostC-increased levels of Akt phosphorylation. Conclusion RIPostC may inhibit the expression of RAGE and HMGB1 and activate PI3K/Akt signaling pathway to extenuate ischemic reperfusion injury in mice. It could further suppress the oxidative stress, have antiapoptosis effect, and reduce inflammatory reaction, but this effect has certain timeliness.