缺血后适应应用于心肌梗死介入治疗的研究进展

缺血后适应的心脏保护作用是医学界的重大发现。缺血后适应是一系列机械性和化学性机制联合作用而产生的结果,其具有一系列通过再灌注早期所激活的代谢通路的主动保护效果,它们的终末效应器是线粒体ATP敏感性钾通道(mitoKATP)和线粒体mPTP孔道。缺血后适应干预有一个时间窗,即在再灌注开始的数分钟内有效,而且再灌注最初几分钟对于再灌注损伤的下游机制的影响是至关重要的。然而,对于采取何种缺血后适应方案可以达到心脏保护的最大效果,目前仍缺乏统一的观点,笔者尝试对常用的几种方案进行相关探讨。     

缺血后适应对糖尿病大鼠再灌注心肌的保护作用及其与P-Akt的关系

目的:探讨缺血后适应对糖尿病大鼠离体心脏缺血再灌注损伤的影响及其信号机制。方法:2W龄健康SD大鼠60只,雌雄不拘,体质量250～300g,随机分为6组:1.空白对照组(N组);2.缺血再灌注组(IR组);3.缺血后适应组(Post组);4.糖尿病大鼠后适应组(Dpost组);5.糖尿病大鼠缺血再灌注组(DIR组);6.糖尿病大鼠空白组(DN组)。观测心脏冠状动脉灌流量、心肌梗死范围、免疫印迹(western blot)对P-Akt的测定、电镜下观察心肌和线粒体的改变。结果:缺血后适应组(Post组DPost组)较缺血再灌注组(IR组DIR组)冠状动脉流量明显增加,心肌梗死范围明显减少,P-Akt的表达明显增强,心肌纤维和线粒体的完整程度明显较好。结论:缺血后处理在糖尿病大鼠离体心脏具有显著的保护作用,这一作用可能与Akt激活有关。     

缺血后适应心肌线粒体能量代谢研究

目的研究缺血后适应心肌线粒体能量代谢特点。方法以Langendofff离体心脏灌注系统构建缺血后适应大鼠模型，随机分为对照组．再灌注组和后适应组，每组16只。平衡20min后，对照组灌注60min;再灌注组停灌30min，再灌注30min；后适应组停灌30min之后，循环6次再灌注10s，停灌10s，再灌注28min。记录心率和冠状动脉流量。冉灌注末取心肌．用高效液相色谱法测定高能磷酸化合物三磷腺苷、二磷腺苷和一磷腺苷含量；用差速离心法提取心肌线粒体，用氧电极法测定线粒体3态呼吸、4态呼吸和线粒体呼吸控制率。结果与再灌注组比较，后适应组明显提高再灌注末的心率和冠状动脉流量，明显提高心肌内二磷腺苷和一磷腺苷含量，三磷腺苷在各组差异无统计学意义。线粒体3态呼吸和线粒体呼吸控制率改善。结论心肌线粒体能量代谢改善，是缺血后适应心肌保护的可能机制之一。     

后适应能抑制线粒体渗透性转换孔

短期缺血立即进行再灌注能减少梗死面积,此现象被称为后适应（post conditioning）,恢复灌注后,线粒体渗透性转换孔（permeability transition pore）开放与致死性再灌注损伤有关。我们设想后适应可能与调整线粒体渗透性转换孔的开放有关。因此进行如下的实验,麻醉开胸兔经历30分钟缺血和4小时再灌注,后适应包括4次堵塞冠状动脉,每次1分钟和在长期缺血后复流1分钟。     

临床应用心肌缺血预适应与后适应的哲学理论

及时恢复缺血区的血液灌注即再灌注是临床上挽救缺血心肌的最有效措施,但再灌注会引起严重的再灌注损伤。心肌缺血预适应和后适应可以减轻缺血再灌注损伤后心肌的坏死与心肌功能障碍,减少恶性心律失常的发生,是减轻缺血再灌注损伤的有效内源性保护手段。心肌缺血预适应和后适应的机制主要是通过诱导触发因子释放,经多条细胞内信号转导途径的介导,作用于多种效应器,影响缺血再灌注损伤的关键环节而发挥心肌细胞保护作用。心肌缺血预适应和后适应是内因和外因的辩证统一,也蕴含矛盾双方互相转化的规律。     

缺血预适应与心脏外科

缺血预适应(ischemic preconditioning,IP)是指持续心肌缺血前1次或数次短时间缺血和再灌注可以保护随后长时间心肌缺血和再灌注损伤,减少心肌梗死范围并改善心功能.理想的IP模型应当既简单易行,又可最大限度的保护心肌免受缺血-再灌注损伤.IP在心脏外科中的应用已取得一定进展,其分子传导机制尚不完全明了[1].本文介绍IP在心脏外科中应用的新进展.     

心肌缺血后适应的保护作用及机制研究进展

急性心肌梗死发病率的增高,促进了再灌注治疗如溶栓及经皮冠脉介入治疗的应用.这却引起了心肌细胞死亡、血流动力学障碍、再灌注心律失常及内皮功能障碍等缺血再灌注损伤[1].众多研究证实,缺血后适应对缺血再灌注损伤心肌具有保护作用,能够降低梗死面积[2]、减少细胞凋亡[3]、改善内皮功能[4]及减轻组织的水肿[4]等.缺血后适应,即在心肌缺血再灌注的即刻对冠脉进行短暂、重复的开通及再闭过程,随后恢复冠状动脉血流[4].后适应的可操作性,决定了其在临床中应用的可能性.本文就后适应在心肌缺血再灌注损伤中的保护应用及其机制进行综述.     

黄芪注射液预适应对大鼠实验性心肌缺血再灌注损伤的保护作用及其机制

目的探讨黄芪注射液预适应对大鼠实验性缺血/再灌注损伤的保护作用及其作用机制。方法 Wistar大鼠30只,随机分成五组:假手术组、模型组、黄芪注射液治疗组、黄芪注射液+5-羟癸酸钠(5-HD)组、预适应组;采用结扎大鼠左冠状动脉前降支法制备心肌缺血/再灌注损伤模型。测定缺血/再灌注前黄芪注射液预处理对损伤大鼠血清中LDH、MDA和SOD生成的影响,对比心电图的变化;HE染色光镜检测心肌组织形态学变化、TUNEL法检测各组大鼠心肌细胞凋亡率,检测黄芪的干预作用。结果与模型组比较,黄芪注射液抑制大鼠血清中LDH、MDA生成(P0.05),提高SOD的活力(P0.05),降低缺血再灌注损伤大鼠心律失常发生率(P0.05或P0.01),减少损伤大鼠心肌细胞凋亡的发生(P0.01),稳定损伤心肌细胞的结构。线粒体ATP敏感钾通道抑制剂5-HD减弱了黄芪注射液的保护作用。结论黄芪注射液可以减轻大鼠缺血/再灌注损伤,其作用机制可能与激活mitoKATP通道,抑制心肌细胞凋亡有关。     

缺血后适应对兔心肌细胞凋亡的影响

目的 探讨缺血后适应对兔心肌梗死面积及细胞凋亡的影响.方法 32只成年新西兰雄性大白兔接受缺血30 min再灌注3 h,随机分为缺血再灌注组、缺血后适应组、缺血后适应+wortmannin(PI3K阻滞剂)组、缺血再灌注+wortmannin组.采用Evans蓝和TTC染色的方法确定缺血心肌面积以及梗死心肌面积,采用TUNEL法检测凋亡心肌细胞.结果 与缺血再灌注组比较,缺血后适应组梗死心肌面积百分比及凋亡心肌细胞百分比显著减低(均P<0.05).而在后适应+wortmannin 组无明显减低(P>0.05).结论 缺血后适应可以有效地减少缺血再灌注兔心肌梗死面积细胞凋亡百分比,wortmannin抑制了后适应的作用,提示PI3K的活化在缺血后适应中具有重要作用.     

血管紧张素转换酶抑制剂预适应抗心律失常作用研究进展

血管紧张素转换酶抑制剂具有药理性预适应作用 ,能够减轻缺血再灌注后心肌心律失常的发生。血管紧张素转换酶抑制剂预适应抗心律失常的机制从电生理学上认为血管紧张素转换酶抑制剂通过改变缺血期和再灌注期心肌细胞的电活动 ,影响心肌细胞电稳定性 ;从内源性机制上认为血管紧张素转换酶抑制剂通过减少血管紧张素Ⅱ的生成 ,减慢缓激肽的降解增加缓激肽的积聚 ,进而通过BK B2受体途径激活内源性保护机制 ,发挥抗心律失常作用。     

Myocardial apoptosis and ischemic preconditioning

Necrosis and apoptosis are two forms of cell death in the myocardium that have been associated with ischemia and reperfusion. Although it has been well documented that necrosis, as a major form of myocyte cell death, rapidly leads to a destruction of a large group of cells after myocardial ischemia and reperfusion, the induction of apoptosis in myocardium, primarily triggered during reperfusion, may independently contribute to the extension of cell death (i.e. infarction) in a dynamic manner. Ischemic preconditioning (IP), an endogenous protective mechanism rapidly evoked by a brief period of ischemia, is recognized for its protection in limiting myocardial necrosis, but has also shown a profound inhibition in apoptosis. While much research has been done on the reduction of necrosis by IP, there remains no clear understanding of the time course of inhibition of apoptosis by IP after long-term reperfusion. In this review, we will show the time course of necrosis and apoptosis during reperfusion, focus on the role of apoptosis in the extension of lethal myocyte injury, and summarize the potential mechanisms involved in reducing apoptosis by IP. 'Classic' or 'early' IP has been shown to reduce apoptosis in part by inhibiting inflammatory cell activation and altering the expression of anti- and pro-apoptotic proteins as well as protein kinase C activity. It remains unknown, however, whether delayed IP participates in the attenuation of apoptosis in addition to necrosis. The demonstration of a 'window of opportunity' in inhibiting apoptosis by IP will provide new directions in research investigating mechanisms underlying myocyte cell death during reperfusion, and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.     

Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart

This brief review summarizes the recently obtained evidence which illustrates the beneficial effects of the endogenously produced antioxidant, melatonin, in reducing tissue damage and reversing cardiac pathophysiology in models of experimental ischemia/reperfusion. The report also describes the actions of other antioxidants, especially vitamin E and antioxidative enzymes, in altering the degree of ischemia/reperfusion damage in the heart. Based on the data available, melatonin seems to have advantages over other antioxidants tested in terms of ameliorating the hypoxia and reoxygenation-induced damage. While the bulk of the studies that have used melatonin to overcome cardiac injury following transient arterial occlusion and subsequent reperfusion have used pharmacological doses to achieve protection, two recent reports have further shown that merely reducing endogenous circulating concentrations of melatonin (by surgical removal of a source of melatonin, i.e. the pineal gland) exaggerates the degree of injury and reduces survival of animals as a result of induced ischemia/reperfusion of the heart. These findings are consistent with observations in other organs where the loss of physiological concentrations of melatonin results in increased oxidative damage during hypoxia and reoxygenation. These findings have implications for the elderly since in the aged endogenous levels of melatonin are naturally reduced thereby possibly predisposing them to more severe cardiac damage during a heart attack. To date, the bulk of the studies relating to the protective actions of melatonin in reducing cardiac ischemia/reperfusion injury have used the rat as the experimental model. Considering the high efficacy of melatonin in limiting ischemia/reperfusion damage as well as melatonin's low toxicity, the studies should be expanded to include other species and models of cardiac ischemia/reperfusion. The results of these investigations would help to clarify the potential importance of the use of melatonin in situations of oxidative damage to the heart in humans.     

Modulation of liver oxidant-antioxidant system by ischemic preconditioning during ischemia／reperfusion injury in rats

AIM: To investigate effects of ischemic pre-conditioning on the liver endogenous oxidant-antioxidant system during ischemia/reperfusion injury. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into sham-operated (Sham), ischemia/ reperfusion (I/R), ischemic pre-conditioning plus ischemia/ reperfusion (IPC) groups. Serum ALT, AST and hyaluronic acid levels were assayed and pathologic alterations observed. Liver malondialdehyde (MDA) contents, endogenous antioxidant enzymes, superoxidase dismutase (SOD), catalase (CAT), gultathionine peroxidase (GSH-Px) activities, neutrophils accumulation marker, myeloperoxidase (MPO) activities were measured respectively. RESULTS: Compared with I/R group, sinusoidal endothelial cells as well as hepatocytes damages, as assessed biochemically and histochemically, were improved significantly in IPC group; neutrophils infiltration was also markedly reduced. In IPC group, liver peroxidation, as measured by MDA contents, was significantly decreased when compared with I/R group; endogenous antioxidant enzymes, SOD, CAT and GSH-Px activities were markedly higher than that in I/R group. CONCLUSION: Ischemic pre-conditioning exerts protective effects on both hepatic sinusoidal endothelial cells and hepatocytes during liver I/R injury. Its mechanisms may involve dimunition of neutrophils infiltration and modulation of the imbalance of endogenous oxidant-antioxidant system in the organism.     

Advances in intervention methods and brain protection mechanisms of in situ and remote ischemic postconditioning

Ischemic postconditioning (PostC) conventionally refers to a series of brief blood vessel occlusions and reperfusions, which can induce an endogenous neuroprotective effect and reduce cerebral ischemia/reperfusion (I/R) injury. Depending on the site of adaptive ischemic intervention, PostC can be classified as in situ ischemic postconditioning (ISPostC) and remote ischemic postconditioning (RIPostC). Many studies have shown that ISPostC and RIPostC can reduce cerebral IS injury through protective mechanisms that increase cerebral blood flow after reperfusion, decrease antioxidant stress and anti-neuronal apoptosis, reduce brain edema, and regulate autophagy as well as Akt, MAPK, PKC, and KATP channel cell signaling pathways. However, few studies have compared the intervention methods, protective mechanisms, and cell signaling pathways of ISPostC and RIPostC interventions. Thus, in this article, we compare the history, common intervention methods, neuroprotective mechanisms, and cell signaling pathways of ISPostC and RIPostC.

     

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。     

缺血后处理的研究现状

心肌缺血后长时间的冠状动脉再灌注前对缺血心肌进行反复、短暂的再缺血干预,以减轻再灌注损伤,称为缺血后处理。它是缺血心脏有效的内源性保护现象,可以减轻缺血-再灌注后心肌坏死与功能障碍,减少恶性心律失常的发生。人们对其发生机理、信号通路以及潜在的临床应用等方面已作了较多研究。现对缺血后处理的研究现状做一综述。     

bFGF and TGFβ expression in rat kidneys after ischemic/ reperfusional gut injury and its relationship with tissue repair

INTRODUCTION Intestinal ischemia/ reperfusion ( I/ R ) occur commonly in critically ill patients. It is well recognized that gut I/R may cause tissue damage and dysfunction of intestine, and induce remote organ injury including kidney, lung, and liver[1]. It may also lead to complications after severe burn or injury. Previous studies have focused on cellular elements, cytokines and inflammatory mediators.Relatively little attention has been paid endogenous protective mechanisms, I.e. The growth factors.     

Melatonin receptor‐mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1

Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl‐2 expression and downregulating Bax, caspase‐3 and cleaved caspase‐3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91^phox expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R‐induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor‐dependent manner.     

心肌缺血后处理研究进展

缺血后处理是在长时间缺血后再灌注早期对心脏进行数次短暂的再灌注/缺血处理的方法。它是缺血心脏有效的内源性保护现象,可以减轻缺血/再灌注后心肌坏死与功能障碍,减少恶性心律失常的发生。人们对其发生机理、信号通路以及潜在的临床应用等方面已作了较多研究。现对缺血后处理的特征、心肌保护作用、分子机制以及临床应用前景作一综述。     

Verapamil protection of ischemic isolated rabbit heart: dependence on pretreatment

Verapamil may protect ischemic myocardium by several mechanisms: prevention of Ca overload as a direct effect of blocking Ca influx through slow channels, coronary vasodilatation, decreased contractility, or cardioplegia produced by high doses. We manipulated the experimental situation to ask whether the first mechanism alone could be protective. We studied isovolumically contracting rabbit hearts perfused at 37 degrees C, paced at 150/min, and maximally vasodilated by dipyridamole. Hearts were subjected to 60 min of low flow ischemia followed by 60 min reperfusion. Two groups were exposed to verapamil 0.5 microM beginning either 2 to 4 min before ischemia or 10 min after the onset of ischemia (when pressure development had ceased) and continuing until reperfusion. Developed pressure recovered during reperfusion to 70 +/- 4% of its initial value in hearts treated with verapamil before ischemia compared to 40 +/- 5% for control hearts and 35 +/- 11% for hearts treated with verapamil 10 min after the onset of ischemia. There was significant preservation of phosphocreatine at 10 min of ischemia and of ATP at 60 min in the early verapamil group compared to the other two. When verapamil was present before ischemia, pressure development during early ischemia was reduced to about 50% of control. Consequently there was substantial sparing of high energy phosphates and enhanced recovery of mechanical function. If verapamil was added 10 min after the onset of ischemia, when it no longer could affect cardiac work, there was no protection. Therefore, in the isolated rabbit heart, verapamil had an important protective effect only by reducing contractility of ischemic myocardium.