氧自由基在再灌注心肌损伤中的作用

血栓溶解疗法,经皮冠状动脉内血管成形术和冠状动脉搭桥术是目前缺血性心脏病治疗的主要手段。这些措施均可使缺血心肌恢复血流灌注,改善心肌功能。但是再灌注在给缺血心肌带来巨大益处的同时,往往还对缺血心肌产生严重的再灌注性损伤。常见的心肌损伤表现为再灌注心律失常和心肌顿抑,严重时可造成心肌细胞死亡。现一般认为再灌注损伤与缺血心肌再灌时氧自由基的大量产生有关,氧自由基可能是再灌注心肌损伤的重要机制之一。     

锌对缺血再灌注损伤家兔心肌金属硫蛋白-1基因表达的影响

目的研究锌对家兔心肌缺血再灌注损伤的保护作用。方法采用RT-PCR技术,检测分析金属硫蛋白-1(MT-1)基因在家兔缺血再灌注损伤心肌的表达及锌对其基因表达的调节。结果各组家兔心肌组织中均有MT-1基因的表达,缺血再灌注组MT-1基因的表达较正常对照组明显下降(P<0.01),补锌再灌注组MT-1基因的表达较缺血再灌注组明显上调(P<0.01)。结论锌对家兔心肌缺血再灌注损伤的分子机制中,调节其心肌组织中MT-1基因转录水平的表达可能是一条重要途径。     

心肌再灌注的后果

七十年代推广使血管再通的冠脉搭桥术以来对于早期再灌注可使心肌硬塞面积缩小的报导较多,其有害之处则是加速细胞的损伤,而氧自由基是细胞损伤的重要介体。一、经再灌注抢救缺血心肌对缺血心肌重建血供是减少坏死和限制     

激光心肌血运重建术与血管内皮生长因子基因治疗慢性缺血性心脏病的对比研究

目的:探索激光生物效应和血管内皮生长因子(VEGF)基因治疗促进缺血区血管再生的作用。方法:心肌缺血模型猪分别进行激光心肌血运重建术(TMLR)和PcDNA3·1VEGF165基因治疗,6周后行冠状动脉造影、单光子发射型计算机断层扫描(SPECT)、逆转录-聚合酶链反应(RT-PCR)病理学检查。结果:TMLR、基因治疗组冠状动脉造影显示侧支循环明显改善,SPECT显示缺血侧壁灌注显著改善,RT-PCR显示TMLR组VEGF基因有中度表达,基因治疗组有高度或中度表达,心肌血管面积、血管周长、血管数目明显增加(P<0·05);TMLR组血管管径≤25μm数目比基因组明显增加(P<0·05)。结论:TMLR或VEGF基因治疗可以增加心肌血管密度并改善缺血心肌的灌注;TMLR疗效优于VEGF心肌直接注射。     

远端缺血预处理对心肌保护作用的研究现状及进展

急性ST段抬高型心肌梗死患者应尽早进行再灌注治疗,但梗死相关血管的再通可导致缺血再灌注损伤.远端缺血预处理(RIPC)作为近年来比较新颖的概念,能保护心肌免于缺血再灌注损伤,并减少心肌梗死的面积.本文对远端缺血预处理的心肌保护机制和临床应用进展予以阐述.     

心肌缺血再灌注损伤进展

缺血-再灌注损伤指的是在组织器官缺血恢复血流后,不仅没使组织器官功能恢复,反而使缺血所致的功能和代谢障碍及结构破坏进一步加重,甚至出现不可逆损伤的现象。研究最多的就是心肌缺血-再灌注损伤。随着溶栓、冠状动脉搭桥术、经皮冠状动脉内成形术等血管再灌注疗法通过恢复缺血组织的供血有效挽救濒死心肌。但是再灌注受缺血组织血管再通时间限制并存在再灌注损伤等问题,因此随着新的再灌注技术在临床广泛应用,防治心肌缺血-再灌注损伤成为冠心病治疗亟待解决的关键问题之一。     

血管紧张素-(1-7)对心肌肥厚大鼠体外心脏缺血再灌注损伤的影响

目的探讨血管紧张素-(1-7)对心肌肥厚大鼠体外心脏缺血再灌注损伤的影响。方法通过腹主动脉结扎制作大鼠心肌肥厚模型,并用Langendorff装置建立心肌肥厚大鼠体外心脏缺血再灌注模型,观察血管紧张素-(1-7)对心肌肥厚大鼠体外缺血再灌注心脏左心室收缩压、冠状动脉流量、肌酸磷酸激酶和乳酸脱氢酶释放、心肌梗死范围的影响。结果与缺血再灌注对照组相比,血管紧张素-(1-7)处理组心脏左心室收缩压、冠状动脉流量显著提高,冠状动脉循环流出液中肌酸磷酸激酶、乳酸脱氢酶含量降低,心肌梗死范围减小。血管紧张素-(1-7)受体拮抗剂A779能够消除血管紧张素-(1-7)的这种心脏保护作用。结论血管紧张素-(1-7)能够减轻心肌肥厚大鼠体外心脏缺血再灌注损伤,其作用通过其特异性受体介导。     

心肌缺血再灌注损伤时心肌心钠素和血管紧张素Ⅱ的变化及其病理生理意义

在离体大鼠心脏模拟的缺血模型上,发现心肌心钠素(ANF)和血管紧张素Ⅱ(AGTⅡ)含量显著增加,但ANF/AGTⅡ比值仍维持正常,再灌注时心肌AGTⅡ含量进一步增加,ANF/AGTⅡ比值显著降低。应用AGTⅡ再灌注缺血心脏,显著加重其再灌注损伤,而用转换酶抑制剂或ANF再灌注则减轻其再灌注损伤。结果提示,心肌ANF和AGTⅡ的相互作用影响心肌缺血再灌注损伤的发病过程。     

卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及其机制探讨

腹主动脉缩窄致大鼠心肌肥厚模型作离体工作心脏灌流，观察卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及血管紧张素Ⅱ（ＡｎｇⅡ）的影响。结果表明：在心脏停跳液及再灌注Ｋ－Ｈ液中加入卡托普利（２３．０μｍｏｌ／Ｌ）可明显改善肥厚心肌缺血再灌注后心功能的恢复，增加冠状动脉血流量，降低心肌组织乳酸、Ｎａ＋、Ｃａ２＋及ＭＤＡ的含量，并使心肌组织ＣＫ酶峰前移；而ＡｎｇⅡ（１０ｎｍｏｌ／Ｌ）可减弱卡托普利对肥厚心肌受缺血再灌注损伤的保护作用。我们认为，卡托普利对肥厚心肌受缺血再灌注损伤有保护作用，其机制可能与抑制心脏肾素－血管紧张素系统有关     

诱导型一氧化氮合酶在心肌缺血/再灌注损伤中的研究进展

采用溶栓疗法、动脉搭桥术、冠状动脉血管成形术等技术,使缺血组织和器官重新恢复血流,挽救了众多危急重病人的生命,然而,缺血器官及组织在恢复血流的同时,均伴随着缺血/再灌注损伤,是目前临床上亟待解决的问题。在对心血管疾病的研究过程中,随着心肌保护研究的不断深入,如何减轻心肌缺血/再灌注损伤成为心肌保护问题的关键。越来越多的研究表明,心肌缺血/再灌注损伤与诱导型一氧化氮合酶表达过量一氧化氮紧密相关。研究表明,诱导型一氧化氮合酶既有心肌保护作用,也有促心肌损伤作用,而通过对诱导型一氧化氮合酶抑制剂的应用,有望减轻心肌损伤的进展,保护损伤心肌。     

Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury

Exocytosis of endothelial granules promotes thrombosis and inflammation and may contribute to the pathophysiology of early reperfusion injury following myocardial ischemia. TAT-NSF700 is a novel peptide that reduces endothelial exocytosis by inhibiting the ATPase activity and disassembly activity of N-ethylmaleimide-sensitive factor (NSF), a critical component of the exocytic machinery. We hypothesized that TAT-NSF700 would limit myocardial injury in an in vivo murine model of myocardial ischemia/reperfusion injury. Mice were subjected to 30 minutes of ischemia followed by 24 hours of reperfusion. TAT-NSF700 or the scrambled control peptide TAT-NSF700scr was administered intravenously 20 minutes before the onset of ischemia. Myocardial ischemia/reperfusion caused endothelial exocytosis, myocardial infarction, and left ventricular dysfunction. However, TAT-NSF700 decreased von Willebrand factor levels after myocardial ischemia/reperfusion, attenuated myocardial infarct size by 47%, and preserved left ventricular structure and function. These data suggest that drugs targeting endothelial exocytosis may be useful in the treatment of myocardial injury following ischemia/reperfusion.     

微小RNA对缺血再灌注损伤心肌线粒体作用的研究进展

心肌缺血再灌注损伤是造成心肌结构损伤、功能障碍的一种病理生理过程,进一步发展会导致级联的多器官功能障碍。线粒体是一种结构功能复杂且对外界环境反应敏感的细胞器,其稳态的维持依赖于正常形态、功能及数量的相对稳定状态。线粒体质量与代谢异常和心血管疾病尤其是心肌缺血再灌注损伤的发生密切相关。微小RNA是近年来研究较多的在缺血再灌注损伤心肌线粒体保护中具有重要作用的调控因子。本文通过微小RNA对心肌缺血再灌注损伤时线粒体形态、功能、线粒体自噬和线粒体DNA几个方面的调控机制与相关前沿进展进行综述,为微小RNA参与缺血再灌注心肌线粒体损伤的后续研究提供一定的理论依据。     

Myocardium reperfusion injury

The phenomenon of ischemia/reperfusion injury is described in the experimental models of acute myocardial infarction（AMI）,causing additional functional and structural damage to the acute reperfused myocardium,and ischemic preconditioning refers to the myocardial ischemia after a long period of reperfusion before one or several shortoccasional duplication of myocardial ischemia /reperfusion1,which can increase myocardial ischemic tolerance.The therapeutic strategies for AMI have focused on myocardial ischemia /reperfusion injury,which accounts for a significant part of the final infarct size.Although experiments in the last 20 years have reported that pharmacological interventions at reperfusion might reduce myocardial reperfusion injury,this could not be confirmed in human studies.An alternative to chemical modifiers,postconditioning（brief repeated periods of ischemia applied at the onset of reperfusion） is another method proven to be efficient in animal models and to be confirmed in recent human studies.This simple method,applied in the first minute of reperfusion,reduces the final infarct size by 30%-50%.This review will focus on the mechanisms,pharmacological preconditioning,postconditioning technique,which is easily applicable in human patients in the setting of AMI.     

用小型猪研究心肌缺血再灌注损伤的机制

应用小型猪在体心脏缺血再灌注(IR)模型,探讨心肌IR损伤机制。发现心肌IR后有下列变化:①心肌细胞内钙、钠增多,钾减少。②心肌细胞膜流动性降低及冠状窦静脉血化学发光增强,间接显示自由基产生增多。③白细胞激活后产生氧自由基的反应增强,提示白细胞可能参与IR损伤机制。     

再灌注损伤挽救激酶和生存活化因子增强信号通路在心肌缺血再灌注损伤中的研究进展

经皮冠状动脉介入治疗、溶栓治疗可以使心肌梗死患者明显获益并且改善预后,但是由此引起的心肌缺血再灌注损伤问题也凸显出来,心肌缺血再灌注损伤涉及到多个靶点通路,不同信号通路之间的关系错综复杂。近几年医学家提出的再灌注损伤挽救激酶和生存活化因子增强两个促存活激酶信号通路成为了再灌注干预治疗的新靶点,从而成为心血管疾病甚至其他血管性疾病的新的切入点。本文拟阐述这两条信号通路对缺血再灌注后心肌保护的作用机制,为心肌梗死新药研发提供新思路。     

盐酸法舒地尔后适应对大鼠心肌缺血再灌注损伤的保护作用

目的通过主动脉根部模拟冠状动脉内给药,观察盐酸法舒地尔后适应对大鼠急性心肌缺血再灌注损伤的保护作用。方法选择SD大鼠48只,随机分为假手术组、缺血再灌注组、缺血后适应组、法舒地尔组,每组12只。各组于再灌注3 h后处死大鼠,分别测定心功能参数、血浆心肌酶、心肌梗死范围和心肌细胞凋亡指数。结果与假手术组比较,缺血再灌注组、缺血后适应组和法舒地尔组血浆心肌酶含量明显升高,差异有统计学意义(P<0.01)。与缺血再灌注组比较,法舒地尔组心功能参数明显改善,血浆心肌酶含量、心肌梗死范围、心肌细胞凋亡指数明显下降,差异有统计学意义(P<0.01)。结论盐酸法舒地尔可以模拟缺血后适应效应,减轻心肌缺血再灌注损伤,减少缺血心肌细胞凋亡,缩小心肌梗死范围。     

Fas/FasL系统与心肌缺血再灌注细胞凋亡

心肌缺血再灌注损伤与众多凋亡基因密切相关.Fas/FasL系统在心肌缺血再灌注损伤中起关键作用,是引起细胞凋亡的主要途径之一,是直接启动细胞凋亡信号传导的系统之一.Fas/FasL系统与心肌缺血再灌注细胞凋亡及其信号传导机制是目前国内外研究的热点,现对该问题做一综述.     

细胞凋亡与心肌缺血/再灌注损伤

近年研究发现细胞凋亡与心肌缺血/再灌注损伤关系密切,可能是其发病机制之一。现就心肌缺血/再灌注损伤中细胞凋亡发生的原因、参与调控的相关基因及信号途径作一综述。     

The Antioxidant,N-(2-mercaptopropionyl)-glycine (MPG), Does Not Reduce Myocardial Infarct Size in an Acute Canine Model of Myocardial Ischemia and Reperfusion

Oxygen radical generation can be measured when blood flow is restored to previously ischemic tissue. Although several studies have suggested oxygen radicals contribute to lethal injury of myocardium after ischemia, other studies have failed to confirm this implication. Antioxidants, such as N-(2-mercaptoptopionyl)-glycine (MPG) and superoxide dismutase, have had inconsistent effects on lethal myocardial injury in animal models of ischemia and reperfusion. Many variables influence lethal myocardial injury in these models: time of ischemia, time of reperfusion, dose of antioxidant, myocardial oxygen demand, area at risk, collateral blood flow, and body core temperature. The purpose of this study is to test the effects of infusion of MPG on lethal reperfusion injury in a canine model of ischemia and reperfusion with these variables tightly controlled. The left anterior descending coronary artery of anesthetized dogs was ligated for 90 minutes and reperfused for 4 hours. MPG was infused (100 mg/kg/h) 15 minutes before the end of ischemia and throughout reperfusion. Core body temperature was closely monitored, and infarct size was adjusted to transmural myocardial blood flow during ischemia. MPG had no effect on infarct size or infarct size adjusted for changes in collateral blood flow. These data reinforce a general difficulty in demonstrating the effects of antioxidant therapies on lethal injury, even when closely monitoring covariates known to impact infarct size.     

Pharmacological possibilities for protection against myocardial reperfusion injury

Reperfusion through thrombolysis or percutananeous coronary angioplasty is standard treatment in impending acute myocardial infarction. Although restoration of blood flow to the jeopardised myocardial area is a perquisite for myocardial salvage, reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone. This is referred to as the "reperfusion injury". Since the reperfusion injury is initiated by the treatment of myocardial infarction, it is of importance to limit the extent of the injury. Several studies aimed at preventing reperfusion injury by means of pharmacological agents have therefore been conducted. The design of such studies is crucial for the results. Factors of importance are the timing of drug administration, animal species used, the degree of collateral flow and the duration of ischemia. A variety of pharmacological compounds have been investigated in different experimental models of myocardial ischemia and reperfusion. These include oxygen free radical scavengers, antioxidants, calcium channel blockers, inhibitors of neutrophils, nitric oxide, adenosine-related agents, inhibitors of the renin-angiotensin system, endothelin receptor antagonists, Na(+)/H(+) exchange inhibitors, and anti-apoptotic agents. All these groups of pharmacological agents have been demonstrated to protect from reperfusion injury determined as limitation of infarct size, improved myocardial and endothelial function, and reduced incidence of arrhythmias. The mechanism behind the protective effect may differ between different groups of compounds, but some compounds may exert cardioprotection via common pathways. Such a pathway may be via maintained bioavailability of nitric oxide.