Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves op...Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves opening of the mitochondrial permeability transition pore(mPTP).In reperfusion injury,mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability.Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species(ROS).Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning,obtained with brief intermittent ischemia or with pharmacological agents.These pathways converge on a common target,the mitochondria,to preserve their function after ischemia/reperfusion.The present review discusses the role of mitochondria in cardioprotection,especially the involvement of adenosine triphosphate-dependent potassium channels,ROS signaling,and the mPTP.Ischemic postconditioning has emerged as a new way to target the mitochondria,and to drastically reduce lethal reperfusion injury.Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects,and an interesting alternative is pharmacological postconditioning.In fact ischemic postconditioning and the mPTP desensitizer,cyclosporine A,have been shown to induce comparable protection in AMI patients.展开更多
Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postcon...Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postconditioning are unclear. Mitochondrial permeability transition pore (MPTP) opening is a major cause of ischemia-reperfusion injury. Here we investigated sevoflurane- and propofol-induced postconditioning and their relationship with MPTP. Methods: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. During the first 15 min of reperfusion, hearts were treated with either control buffer (CTRL group) or buffer containing 20 μmol/L atractyloside (ATR group), 3% (v/v) sevoflurane (SPC group), 50 μmol/L propofol (PPC group), or the combination of atractyloside with respective anesthetics (SPC+ATR and PPC+ATR groups). Infarct size was determined by dividing the total necrotic area of the left ventricle by the total left ventricular slice area (percent necrotic area). Results: Hearts treated with sevoflurane or propofol showed significantly better recovery of coronary flow, end-diastolic pressures, left ventricular developed pressure and derivatives compared with controls. Sevoflurane resulted in more protective alteration of hemodynamics at most time point of reperfusion than propofol. These improvements were paralleled with the reduction of lactate dehydrogenase release and the decrease of infarct size (SPC vs CTRL: (17.48±2.70)% vs (48.47±6.03)%, P<0.05; PPC vs CTRL: (35.60±2.10)% vs (48.47±6.03)%, P<0.05). SPC group had less infarct size than PPC group (SPC vs PPC: (17.48±2.70)% vs (35.60±2.10)%, P<0.05). Atractyloside coadministration attenuated or completely blocked the cardioprotective effect of postconditioning of sevoflurane and propofol. Conclusion: Postconditioning of sevoflurane and propofol has cardio-protective effect against ischemia-reperfusion injury of heart, which is associated with inhibition of MPTP opening. Compared to propofol, sevofluran展开更多
Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To inve...Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committe展开更多
Background Previous studies suggested that mechanical intervention during early reperfusion, or ischemia postconditioning （Ipo）, could protect kidneys against renal ischemia reperfusion injury （RIRI）. However, the...Background Previous studies suggested that mechanical intervention during early reperfusion, or ischemia postconditioning （Ipo）, could protect kidneys against renal ischemia reperfusion injury （RIRI）. However, the mechanisms responsible for this protection remain unclear. This study therefore investigated the protection afforded by Ipo in rat kidneys in vivo, and the roles of mitochondrial KATP channels （mitOKATP） and mitochondrial permeability transition pores （MPTPs）, by inhibiting mitOKATP with 5-hydroxydecanoate （5-HD）, and by directly detecting open MPTPs using calcein-AM and CoCl2.Methods Thirty-five male Sprague-Dawley rats were randomly assigned to sham-operation （S）, ischemia-reperfusion （I/R）,Ipo, ischemia reperfusion with 5-HD （I/R＋5-HD）, or Ipo with 5-HD （Ipo ＋5-HD） groups. Rats in each group were sacrificed after 6 hours of reperfusion by heart exsanguination or cervical dislocation under anesthesia. RIRI was assessed by determination of creatinine and blood urea nitrogen （BUN）, and by examination of histologic sections. The roles of mitoKATP and MPTP were investigated by analyzing fluorescence intensities of mitochondria, mitochondrial membrane potential,intracellular reactive oxygen species （ROS） and intracellular calcium, using appropriate fluorescent markers. The relationship between apoptosis and RIRI was assessed by determining the apoptotic index （Al） of kidney tubular epithelial cells.Results The RIRI model was shown to be successful. Significantly higher levels of creatinine and BUN, and abnormal pathology of histologic sections, were observed in group I/R, compared with group S. 5-HD eliminated the renoprotective effects of Ipo. Mitochondrial and mitochondrial membrane potential fluorescence intensities increased, and intracellular calcium, ROS fluorescence intensities and AI decreased in group Ipo, compared with group I/R. However, mitochondrial and mitochondrial membrane potential fluorescence intensities decreased, and intracellular cal展开更多
基金Supported by National Institutes of Cardiovascular ResearchRegione Piemonte,PRIN,ex-60% and Compagnia di San Paolo,Italy
文摘Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves opening of the mitochondrial permeability transition pore(mPTP).In reperfusion injury,mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability.Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species(ROS).Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning,obtained with brief intermittent ischemia or with pharmacological agents.These pathways converge on a common target,the mitochondria,to preserve their function after ischemia/reperfusion.The present review discusses the role of mitochondria in cardioprotection,especially the involvement of adenosine triphosphate-dependent potassium channels,ROS signaling,and the mPTP.Ischemic postconditioning has emerged as a new way to target the mitochondria,and to drastically reduce lethal reperfusion injury.Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects,and an interesting alternative is pharmacological postconditioning.In fact ischemic postconditioning and the mPTP desensitizer,cyclosporine A,have been shown to induce comparable protection in AMI patients.
基金Project supported by the National Natural Science Foundation ofChina (No. 30772090)the Natural Science Foundation of ZhejiangProvince (No. Y204141)+2 种基金the Foundation from Science and Technology Department of Zhejiang Province (No. 2007R10034)theFoundation from Personnel Department of Zhejiang Province (NoJ20050046)the Foundation from Health Department of ZhejiangProvince (No. 2007QN007), China
文摘Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postconditioning are unclear. Mitochondrial permeability transition pore (MPTP) opening is a major cause of ischemia-reperfusion injury. Here we investigated sevoflurane- and propofol-induced postconditioning and their relationship with MPTP. Methods: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. During the first 15 min of reperfusion, hearts were treated with either control buffer (CTRL group) or buffer containing 20 μmol/L atractyloside (ATR group), 3% (v/v) sevoflurane (SPC group), 50 μmol/L propofol (PPC group), or the combination of atractyloside with respective anesthetics (SPC+ATR and PPC+ATR groups). Infarct size was determined by dividing the total necrotic area of the left ventricle by the total left ventricular slice area (percent necrotic area). Results: Hearts treated with sevoflurane or propofol showed significantly better recovery of coronary flow, end-diastolic pressures, left ventricular developed pressure and derivatives compared with controls. Sevoflurane resulted in more protective alteration of hemodynamics at most time point of reperfusion than propofol. These improvements were paralleled with the reduction of lactate dehydrogenase release and the decrease of infarct size (SPC vs CTRL: (17.48±2.70)% vs (48.47±6.03)%, P<0.05; PPC vs CTRL: (35.60±2.10)% vs (48.47±6.03)%, P<0.05). SPC group had less infarct size than PPC group (SPC vs PPC: (17.48±2.70)% vs (35.60±2.10)%, P<0.05). Atractyloside coadministration attenuated or completely blocked the cardioprotective effect of postconditioning of sevoflurane and propofol. Conclusion: Postconditioning of sevoflurane and propofol has cardio-protective effect against ischemia-reperfusion injury of heart, which is associated with inhibition of MPTP opening. Compared to propofol, sevofluran
基金supported by the National Natural Science Foundation of China,No.81501690(to ZTG)the Scientific Research Staring Foundation for Talent Introduction for Southern Medical University(to MM)
文摘Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committe
基金This study was supported by a grant from Natural Science Foundation of Hebei Province （No. C2011307006）.
文摘Background Previous studies suggested that mechanical intervention during early reperfusion, or ischemia postconditioning （Ipo）, could protect kidneys against renal ischemia reperfusion injury （RIRI）. However, the mechanisms responsible for this protection remain unclear. This study therefore investigated the protection afforded by Ipo in rat kidneys in vivo, and the roles of mitochondrial KATP channels （mitOKATP） and mitochondrial permeability transition pores （MPTPs）, by inhibiting mitOKATP with 5-hydroxydecanoate （5-HD）, and by directly detecting open MPTPs using calcein-AM and CoCl2.Methods Thirty-five male Sprague-Dawley rats were randomly assigned to sham-operation （S）, ischemia-reperfusion （I/R）,Ipo, ischemia reperfusion with 5-HD （I/R＋5-HD）, or Ipo with 5-HD （Ipo ＋5-HD） groups. Rats in each group were sacrificed after 6 hours of reperfusion by heart exsanguination or cervical dislocation under anesthesia. RIRI was assessed by determination of creatinine and blood urea nitrogen （BUN）, and by examination of histologic sections. The roles of mitoKATP and MPTP were investigated by analyzing fluorescence intensities of mitochondria, mitochondrial membrane potential,intracellular reactive oxygen species （ROS） and intracellular calcium, using appropriate fluorescent markers. The relationship between apoptosis and RIRI was assessed by determining the apoptotic index （Al） of kidney tubular epithelial cells.Results The RIRI model was shown to be successful. Significantly higher levels of creatinine and BUN, and abnormal pathology of histologic sections, were observed in group I/R, compared with group S. 5-HD eliminated the renoprotective effects of Ipo. Mitochondrial and mitochondrial membrane potential fluorescence intensities increased, and intracellular calcium, ROS fluorescence intensities and AI decreased in group Ipo, compared with group I/R. However, mitochondrial and mitochondrial membrane potential fluorescence intensities decreased, and intracellular cal
