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1.
    
Phosphatidyl-inositol-3-kinase (PI3K)-Akt pathway is essential for conferring cardioprotection in response to ischaemic preconditioning (IPC) stimulus. However, the role of the individual Akt isoforms expressed in the heart in mediating the protective response to IPC is unknown. In this study, we investigated the specific contribution of Akt1 and Akt2 in cardioprotection against ischaemia-reperfusion (I-R) injury. Mice deficient in Akt1 or Akt2 were subjected to in vivo regional myocardial ischaemia for 30 min. followed by reperfusion for 2 hrs with or without a prior IPC stimulus. Our results show that mice deficient in Akt1 were resistant to protection with either one or three cycles of IPC stimulus (42.7 ± 6.5% control versus 38.5 ± 1.9% 1 χ IPC, N = 6, NS; 41.4 ± 6.3% control versus 32.4 ± 3.2% 3 χ IPC, N = 10, NS). Western blot analysis, performed on heart samples taken from Akt1(-/-) mice subjected to IPC, revealed an impaired phosphorylation of GSK-3β, a downstream effector of Akt, as well as Erk1/2, the parallel component of the reperfusion injury salvage kinase pathway. Akt2(-/-) mice, which exhibit a diabetic phenotype, however, were amenable to protection with three but not one cycle of IPC (46.4 ± 5.6% control versus 35.9 ± 5.0% in 1 χ IPC, N = 6, NS; 47.0 ± 6.0% control versus 30.8 ± 3.3% in 3 χ IPC, N = 6; *P = 0.039). Akt1 but not Akt2 is essential for mediating a protective response to an IPC stimulus. Impaired activation of GSK-3β and Erk1/2 might be responsible for the lack of protective response to IPC in Akt1(-/-) mice. The rise in threshold for protection in Akt2(-/-) mice might be due to their diabetic phenotype.  相似文献   

2.
    
The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro‐survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K‐Akt, its negative regulator PTEN and other pro‐survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K‐dependent during the IPC phase. In conclusion, PI3K‐Akt plays a major role in IPC‐induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K‐independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade.  相似文献   

3.
    
Brief and sublethal ischaemia renders an organ tolerant to subsequent prolonged ischaemia, which is called ischaemic preconditioning (IPC). In regard to the beneficial effects and endogenous mechanisms of renal delayed IPC, few data are available. In this study, we aim at determining reno-protective effects of delayed IPC against ischaemia-reperfusion (I/R) injury, and illustrating whether these effects are associated with suppressing inflammation and nuclear factor-kappaB (NF-kappaB) activation. I/R injury was induced by clamping both renal pedicles for 40 min, followed by 24 h of reperfusion. The rats were subjected to ischaemia for 20 min (preconditioning) or sham surgery (non- preconditioning) at day 4 before I/R. Functional and morphological parameters were evaluated at 24 h after reperfusion. At the same time, macrophage (ED-1(+)) infiltration, and the expression of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) were assessed by immunohistochemistry. Moreover, I kappa B-alpha degradation and NF-kappaB/DNA binding activity were analyzed. Compared with rats exposed to I/R injury, preconditioned rats had a significant decrease in levels of serum creatinine (Scr, 384.3 +/- 21.8 micromol/L vs. 52.5 +/- 21.7 micromol/L; p<0.001), blood urea nitrogen (BUN, 40.4 +/- 2.7 mmol/L vs. 15.9 +/- 4.2 mmol/L; p<0.001) and serum aspartate aminotransferase (AST, 486.7 +/- 58.6 IU/L vs. 267.3 +/- 43.9 IU/L; p<0.001). Parallel to the above changes, preconditioned rats preserved structural integrity and decreased tubulointerstitial damage scores (3.4 +/- 0.3 vs. 0.2 +/- 0.05; p<0.001) and ED-1(+) cell infiltration (25.3 +/- 3.5 vs. 6.2 +/- 1.2 cells/HPF, p<0.01). Furthermore, our results showed that the expression of ICAM-1 and TNF-alpha, the degree of I kappa B-alpha degradation, and NF-kappaB/DNA binding activity were reduced by IPC. Taken together, our results demonstrated that delayed IPC offered both functional and histological protection, which may be related to suppression of inflammation in preconditioned kidneys.  相似文献   

4.
内皮素-1预处理时大鼠心脏Gαq/11和Giα蛋白含量的变化   总被引：1，自引：0，他引：1  
探讨内皮素 1预处理和缺血预处理两种预处理方式与G蛋白有关的信号转导途径的异同。用 0 5nmol/ml内皮素 1左心室注射或夹闭左冠状动脉 5min/再灌 5min× 2进行预处理 ,然后两组均缺血 6 0min ,再灌 30min。观察心电变化 ,免疫印迹法测定心脏Gαq/11和Giα2的含量。结果显示 ,无论是内皮素 1预处理还是缺血预处理均明显减轻缺血再灌注性室性心律失常。与对照组相比 ,缺血预处理组Gαp/11含量升 77 8% (P <0 0 5 ) ,Giα2含量无明显改变。内皮素 1预处理组Gαq/11含量升高 110 6 % (P <0 0 1) ,Giα2含量下降 31 0 % (P <0 0 5 )。本研究结果提示 ,激活Gαq/11蛋白是两种预处理对心肌产生保护作用的共同信号转导通路 ,而Giα2蛋白在两种预处理中的作用方式有所不同。  相似文献   

5.
    
Renalase was discovered as a protein synthesized by the kidney and secreted in blood where it circulates at a concentration of approximately 3–5 μg/ml. Initial reports suggested that it functioned as an NAD(P)H oxidase and could oxidize catecholamines. Administration of renalase lowers blood pressure and heart rate and also protects cells and organs against ischaemic and toxic injury. Although renalase's protective effect was initially ascribed to its oxidase properties, a paradigm shift in our understanding of the cellular actions of renalase is underway. We now understand that, independent of its enzymatic properties, renalase functions as a cytokine that provides protection to cells, tissues and organs by interacting with its receptor to activate protein kinase B, JAK/STAT, and the mitogen‐activated protein kinase pathways. In addition, recent studies suggest that dysregulated renalase signalling may promote survival of several tumour cells due to its capacity to augment expression of growth‐related genes. In this review, we focus on the cytoprotective actions of renalase and its capacity to sustain cancer cell growth and also the translational opportunities these findings represent for the development of novel therapeutic strategies for organ injury and cancer.  相似文献   

6.
目的:探讨远端缺血预处理对同种异体肾移植术后患者肾功能的影响。方法:选择行同种异体肾移植手术的患者20例,并将其随机分为实验组(S)和对照组(D),每组10例。S组于麻醉后在左下肢绑扎止血带行远端缺血预处理,D组不作缺血预处理。分别于术前(T0)、术后24(T1)、48(T2)、72h(T3)记录患者的尿量;生化检测患者血清尿素氮(BUN)和肌酐(Scr)含量;ELISA检测患者肾损伤分子-1(Kim-1)的含量。结果:两组患者的一般情况比较无统计学差异(P0.05)。两组患者术后各时点的尿量均较术前显著增加,且S组术后各时点的尿量均明显多于D组增多(P0.05)。两组患者术后各时点的Scr、BUN含量均较术前下降,两组T1、T2时点的Scr、BUN含量比较差异无统计学意义(P0.05),但S组术后T3时点血清Scr、BUN水平均明显低于D组(P0.05)。两组患者术后尿液Kim-1水平均较术前明显下降,S组在T3时点的Kim-1水平显著低于D组(P0.05)。结论:远端缺血预处理可显著减轻移植肾缺血再灌注损伤,有利于同种异体肾移植患者术后肾功能的恢复。  相似文献   

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8.
    
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9.
Hypothermia and hypothermic preconditioning are known to be profoundly cardioprotective, but the molecular mechanisms of this protection have not been fully explained. In this study, temperature preconditioning (16 °C) was found to be cardioprotective in isolated adult rat ventricular myocytes, enhancing contractile recovery and preventing calcium dysregulation after oxidative stress. Hypothermic preconditioning preserved mitochondrial function by delaying the pathological opening of the mitochondrial permeability transition pore (mPTP), whereas transient mPTP flickering remained unaltered. For the first time, reactive oxygen species (ROS) from the mitochondria are shown to be released exclusively during the hypothermic episodes of the temperature-preconditioning protocol. Using a mitochondrially targeted ROS biosensor, ROS release was shown during the brief bursts to 16 °C of temperature preconditioning. The ROS scavenger N-(2-mercaptopropionyl) glycine attenuated ROS accumulation during temperature preconditioning, abolishing the protective delay in mPTP opening. Temperature preconditioning induces ROS-dependant phosphorylation of the prosurvival kinase extracellular signal-regulated kinase (ERK)1/2. ERK1/2 activation was shown to be downstream of ROS release, as the presence of a ROS scavenger during temperature preconditioning completely blocked ERK1/2 activation. The cardioprotective effects of temperature preconditioning on mPTP opening were completely lost by inhibiting ERK1/2 activation. Thus, mitochondrial ROS release and ERK1/2 activation are both necessary to signal the cardioprotective effects of temperature preconditioning in cardiac myocytes.  相似文献   

10.
    
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11.
    
TIM‐4 plays an important role in ischaemia‐reperfusion injury of liver and kidney; however, the effects of TIM‐4 on cerebral ischaemia‐reperfusion injury (IRI) are unknown. The purpose of the present study was to investigate the potential role of TIM‐4 in experimental brain ischaemia‐reperfusion injury. In this study, cerebral ischaemia reperfusion was induced by transient middle cerebral artery occlusion (MCAO) for 1 hour in C57/BL6 mice. The TIM‐4 expression was detected in vivo or vitro by real‐time quantitative polymerase chain reaction, Western blot and flow cytometric analysis. In vivo, the administration of anti‐TIM‐4 antibodies significantly suppressed apoptosis, inhibited inflammatory cells and enhanced anti‐inflammatory responses. In vitro, activated microglia exhibited reduced cellular proliferation and induced IRI injury when co‐cultured with neurons; these effects were inhibited by anti‐TIM‐4 antibody treatment. Similarly, microglia transfected with TIM‐4 siRNA and stimulated by LPS + IFN‐γ alleviated the TIM‐4‐mediated damage to neurons. Collectively, our data indicate that the inhibition of TIM‐4 can improve the inflammatory response and exerts a protective effect in cerebral ischaemia‐reperfusion injury.  相似文献   

12.
    
The insulin‐PI3K‐mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin‐sensitivity via insulin‐PI3K‐mTOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a siRNA (siLin28a) or lin28a cDNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS, improved LV ejection fraction (LVEF), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS, decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre‐treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF1R, p‐Akt, p‐mTOR and p‐p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre‐treatment abolished the effects of increased p‐mTOR and p‐p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS, improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin‐PI3K‐mTOR dependent pathway.  相似文献   

13.
    
Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.  相似文献   

14.
    
Oxidative stress can cause injury in retinal endothelial cells. Carboxymethyl cellulose modified with collagen peptide (CMCC) is of a distinct antioxidant capacity and potentially a good drug carrier. In this study, the protective effects of CMCC against H2O2‐induced injury of primary retinal endothelial cells were investigated. In vitro, we demonstrated that CMCC significantly promoted viability of H2O2‐treated cells, efficiently restrained cellular reactive oxygen species (ROS) production and cell apoptosis. Then, the CMCC was employed as both drug and anti‐inflammatory drug carrier for treatment of retinal ischaemia/reperfusion (I/R) in rats. Animals were treated with CMCC or interleukin‐10‐loaded CMCC (IL‐10@CMCC), respectively. In comparisons, the IL‐10@CMCC treatment exhibited superior therapeutic effects, including better restoration of retinal structural thickness and less retinal apoptosis. Also, chemiluminescence demonstrated that transplantation of IL‐10@CMCC markedly reduced the retinal oxidative stress level compared with CMCC alone and potently recovered the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that CMCC provides a promising platform to enhance the drug‐based therapy for I/R‐related retinal injury.  相似文献   

15.
    
Impaired mitochondrial function is a key factor attributing to lung ischaemia‐reperfusion (IR) injury, which contributes to major post‐transplant complications. Thus, the current study was performed to investigate the role of mitochondrial autophagy in lung I/R injury and the involvement of the mTOR pathway. We established rat models of orthotopic left lung transplantation to investigate the role of mitochondrial autophagy in I/R injury following lung transplantation. Next, we treated the donor lungs with 3‐MA and Rapamycin to evaluate mitochondrial autophagy, lung function and cell apoptosis with different time intervals of cold ischaemia preservation and reperfusion. In addition, mitochondrial autophagy, and cell proliferation and apoptosis of pulmonary microvascular endothelial cells (PMVECs) exposed to hypoxia‐reoxygenation (H/R) were monitored after 3‐MA administration or Rapamycin treatment. The cell apoptosis could be inhibited by mitochondrial autophagy at the beginning of lung ischaemia, but was rendered out of control when mitochondrial autophagy reached normal levels. After I/R of donor lung, the mitochondrial autophagy was increased until 6 hours after reperfusion and then gradually decreased. The elevation of mitochondrial autophagy was accompanied by promoted apoptosis, aggravated lung injury and deteriorated lung function. Moreover, the suppression of mitochondrial autophagy by 3‐MA inhibited cell apoptosis of donor lung to alleviate I/R‐induced lung injury as well as inhibited H/R‐induced PMVEC apoptosis, and enhanced its proliferation. Finally, mTOR pathway participated in I/R‐ and H/R‐mediated mitochondrial autophagy in regulation of cell apoptosis. Inhibition of I/R‐induced mitochondrial autophagy alleviated lung injury via the mTOR pathway, suggesting a potential therapeutic strategy for lung I/R injury.  相似文献   

16.
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17.
    
Interleukin (IL)-7 is known to enhance the macrophages cytotoxic activity and that macrophages play a pivotal role in the development and progression of myocardial ischaemia/reperfusion (I/R) injury. However, the effects of IL-7 on macrophages infiltration and polarization in myocardial I/R injury are currently unclear. This study aimed to evaluate the effects of the IL-7 expression on myocardial I/R injury and their relationship with macrophages. The data showed that IL-7 expression in mouse heart tissue increases following I/R injury and that IL-7 knockout or anti-IL-7 antibody treatment significantly improve I/R injury, including reduction in myocardial infarction area, a serum troponin T level decreases and an improvement in cardiac function. On the other hand, recombinant IL-7 (rIL-7) supplementation induces opposite effects and the anti-IL-7 antibody significantly reduces the cardiomyocyte apoptosis and macrophage infiltration. rIL-7 cannot directly cause apoptosis, but it can induce cardiomyocyte apoptosis through macrophages, in addition to increase the macrophages migration in vitro. Anti-IL-7 antibody affects the cytokine production in T helper (Th) 1 and Th2 cells and also promotes the macrophages differentiation to M2 macrophages. However, anti-IL-7 antibody does not reduce the M1 macrophage number, and it only increases the ratio of M2/M1 macrophages in mice heart tissues after I/R injury. Taking together, these data reveal that IL-7 plays an intensifying role in myocardial I/R injury by promoting cardiomyocyte apoptosis through the regulation of macrophage infiltration and polarization.  相似文献   

18.
目的:分别观察给予HO-1诱导剂和抑制剂对心肌相对缺血再灌注损伤和缺血预适应的影响,探讨HO-1在缺血预适应中的作用.方法:实验动物随机分为对照组(CN)、缺血/再灌损伤组(I/R)、缺血预适应 缺血/再灌损伤组(PC)、HO-1诱导剂 缺血/再灌损伤组(HM)、HO-1抑制剂 缺血预适应组(ZP).心肌缺血/再灌损伤采用相对缺血/再灌损伤模型,缺血预适应则为相对缺血5min恢复5min,反复2次.测定心功能、MDA及HO-1活性变化.结果:HM组HO-1活性升高,心功能恢复率均显著高于IR组(P＜0.01),MDA含量显著低于IR组(P＜0.05).ZP组活性降低,心功能恢复率显著低于PC组(P＜0.05),MDA含量显著高于PC组(P＜0 05).结论:HO-1是缺血预适应释放的内源性活性物质之一.  相似文献   

19.
缺血预处理对大鼠肺缺血/再灌注损伤的保护作用   总被引：6，自引：0，他引：6  
目的 :观察缺血预处理 (IPC)对大鼠肺缺血 /再灌注 (I/R)损伤的保护作用 ,并初步探讨其作用机制。方法 :建立离体大鼠肺灌流模型 ,36只wistar大鼠随机分为对照组、I/R组和IPC组 ,处理完毕后分别测定平均肺动脉压(MPAP)、肺组织湿 /干重比、支气管肺泡灌洗液中肺表面活性物质磷脂及表面张力改变 ,肺组织标本送电镜检查。结果 :①电镜下观察IPC组肺损伤明显减轻。②肺组织湿 /干重比值IPC组为 4.41± 0 .2 4,显著低于I/R组 ,但仍高于缺血前 (P <0 .0 1) ;③IPC组大鼠缺血 1h后MPAP为 ( 1.88± 0 .2 9)kPa ,明显低于I/R组 (P <0 .0 1) ;④IPC组支气管肺泡灌洗液中总磷脂为 ( 2 33 .42± 14.0 5 ) μg/kg ,大聚体为 ( 10 5 .39± 6 .17) μg/kg ,与I/R组相比显著增高 ,但低于对照组 (P <0 .0 1) ,三组之间小聚体含量没有显著差异 ;⑤IPC组表面张力为 ( 36 .88± 3.49)mN/m ,显著低于I/R组 ,与对照组相比则无显著性差异 (P >0 .0 5 )。结论 :缺血预处理对大鼠肺I/R损伤有保护作用 ,保护机制可能与促进肺表面活性物质 (PS)磷脂分泌、改善PS组成 ,从而提高PS功能有关。  相似文献   

20.
    
The objective of this study was to investigate antioxidant and cytoprotective properties of iloprost in a distant organ after ischaemia reperfusion injury. Male Wistar rats were divided into two groups. After application of anesthaesia both hindlimbs were occluded. A 2-h reperfusion procedure was carried out after 60 min of ischemia. Study group (STU) rats (n=10) received 10 microg kg(-1) iloprost in 1 ml of saline from the tail vein 10 min before reperfusion. Control (CON) group rats (n=10) received an equal amount of saline. The rats were sacrificed by injection of a high dose of thiopentone sodium. Blood and tissue samples (right kidneys) were taken for analysis. Differences in malondialdehyde (MDA), myeloperoxidase (MPO), Na+-K+ ATPase and total antioxidant capacity (TAC) between the groups were analysed. MPO, MDA and TAC levels in the sera of CON and STU groups were 1.60+/-0.26 U l(-1), 11.42+/-5.23 nmol ml(-1), 8.30 x 10(-2)+/- 3.93 x 10(-2) nmol ml(-1) h(-1) and 1.07+/-0.11 U l(-1), 7.60+/-1.81 nmol ml(-1) and 0.15+/-3.23 x 10(-2) nmol ml(-1) h(-1) (p=0.0001, p=0.043 and p=0.0001 respectively). MPO, ATPase and MDA levels in kidneys for CON and STU groups were 1.24+/-0.58 U g(-1), 85.70+/-52.05 nmol mg(-1), 17.90+/-7.40 nmol ml(-1) and 0.78+/-0.31 U g(-1), 195.90+/-56.13 nmol mg(-1) and 10.10+/-0.99 nmol ml(-1) (p=0.046, p=0.0001 and p=0.009 respectively). When given prior to reperfusion, the positive effect of iloprost in the attenuation of distant organ reperfusion injury has been demonstrated.  相似文献   

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