氧化应激与心肌细胞缺血再灌注损伤

冠状动脉粥样硬化性心脏病血运重建治疗是挽救缺血心肌的重要治疗方式。但血流恢复本身会引起缺血再灌注损伤,氧化还原失衡是缺血再灌注损伤发生的重要起始因素。心肌细胞各结构参与氧化应激反应的发生。细胞膜结构中富集Caveolin-1的质膜微囊影响NADPH氧化酶的组装、移位和ROS介导的信号转导参与缺血再灌注中氧化还原反应的发生。由复合物I、II、III、IV及电子载体组成的线粒体电子传递链在缺氧-复氧过程中遭到破坏导致电子传递受阻,线粒体膜通透性转换孔持续开放,是细胞中氧自由基过量产生的重要来源。细胞核及线粒体中核酸分子损伤影响结构蛋白正常合成,细胞氧化还原平衡代谢受损,此外位于细胞核中的肌球蛋白还可以作为一种核转录因子调控NOX2的表达,增加氧自由基的合成。JNK、p38MAPK、Egr-1、NF-κB作为氧化应激导致心肌缺血再灌注损伤的通路蛋白参与其中。     

Peroxynitrite in myocardial ischemia-reperfusion injury

Peroxynitrite is a highly reactive oxidant which is produced during reperfusion of the ischemic heart. The role that this molecule plays in reperfusion injury has been controversial. Many investigations have demonstrated toxic effects of peroxynitrite, whereas others have found it to be protective during reperfusion. This review surveys evidence supporting both sides and proposes that peroxynitrite is a dichotomous molecule with beneficial and detrimental effects on the reperfused heart. Its toxic effects are mediated by modification and activation of a variety of targets (including poly (ADP) ribose synthetase and matrix metalloproteinases) while its beneficial effects are primarily mediated through its reaction with thiols, resulting in the formation of NO donor compounds (S-nitrosothiols).     

Relation between the transmural extent of acute myocardial infarction and associated myocardial contractility two weeks after infarction

To characterize the relation between the transmural extent of acute myocardial infarction (AMI) and associated regional contractility after recovery from ischemia, 11 mongrel dogs underwent occlusion of the proximal left anterior descending coronary artery and were evaluated 2 weeks after infarction. Occlusion was permanent in 5 dogs, and reperfusion was allowed after 2 hours of occlusion in 6 dogs. All dogs had computer-assisted quantitative wall-thickening analysis by 2-dimensional echocardiography and infarct localization by the triphenyl-tetrazolium chloride technique. Percent systolic wall thickening was correlated with the transmural extent of AMI in 40 regions of interest, each measuring approximately 60 arc degrees in circumference. In 11 non-infarct-containing regions, the mean wall thickening was 59 +/- 16% (+/- standard deviation). In 29 infarct-containing segments (with transmural extent of infarction 11 to 100%) systolic wall thickening ranged from -4% to 47%. Wall thickening and transmural extent of AMI were inversely related. Least-squares regression analysis found the relation to be best described by the logarithmic function, percent wall thickening = 61 - 26 log (percent transmural extent of infarction +1), r = -0.87. The nature of this relation between structure and function suggests that salvage of small amounts of myocardium (transmural extent less than 30 to 40%) by coronary reperfusion or other means may have little effect on systolic myocardial function when compared with the function of transmural infarcts. Alternatively, salvage of more than 40% of the jeopardized myocardium should be expected to appreciably augment myocardial function.     

腺苷酸活化蛋白激酶与心肌缺血再灌注损伤

心肌缺血再灌注损伤（MIRI）是指缺血期处于可逆损伤的心肌细胞恢复血液供应后产生更为严重的损伤,主要包括炎症反应、内皮细胞损伤、血流障碍、心肌细胞坏死和凋亡所致心肌梗死面积的扩大、再灌注心律失常、心肌顿抑及冠状微循环障碍等病理生理变化.腺苷酸活化蛋白激酶（5-adenosine monophosphate activated kinase,AMPK）通过调节多种代谢途径控制着心脏能量的供求平衡.AMPK不仅控制葡萄糖和脂类的摄入、储存和利用,还能调节多种代谢酶的活性以及离子通道的开放和相关基因的表达[1].AMPK还能够调节缺血再灌注过程中心肌能量代谢,降低缺血性损伤和心肌凋亡.因此,AMPK被认为是能量应激下心肌细胞代谢调节的关键激酶.     

Metrnl与心肌缺血再灌注损伤的研究进展

镍纹样蛋白(Metrnl)作为一种新的脂肪因子,在人体内广泛分布.心肌缺血后的血运重建引起的心肌缺血再灌注损伤(MIRI)严重影响急性心肌梗死(AMI)患者的治疗预后,而Metrnl与MIRI的改善有着密切关系.该文就Metrnl与MIRI关系的研究进展作一综述.     

Status of myocardial antioxidants in ischemia-reperfusion injury

BACKGROUND: Myocardial ischemia-reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. Injury of myocardium due to ischemia-reperfusion includes cardiac contractile dysfunction, arrhythmias as well as irreversible myocyte damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. OBSERVATIONS: An increase in the formation of reactive oxygen species during ischemia-reperfusion and the adverse effects of oxyradicals on myocardium have now been well established by both direct and indirect measurements. Although several experimental studies as well as clinical trials have demonstrated the cardioprotective effects of antioxidants, some studies have failed to substantiate the results. Nonetheless, it is becoming evident that some of the endogenous antioxidants such as glutathione peroxidase, superoxide dismutase, and catalase act as a primary defense mechanism whereas the others including vitamin E may play a secondary role for attenuating the ischemia-reperfusion injury. The importance of various endogenous antioxidants in suppressing oxidative stress is evident from the depression in their activities and the inhibition of cardiac alterations which they produce during ischemia-reperfusion injury. The effects of an antioxidant thiol containing compound, N-acetylcysteine, and ischemic preconditioning were shown to be similar in preventing changes in the ischemic-reperfused hearts. CONCLUSIONS: The available evidence support the role of oxidative stress in ischemia-reperfusion injury and emphasize the importance of antioxidant mechanisms in cardioprotection.     

MicroRNAs与心肌缺血再灌注损伤

MicroRNAs（miRNAs）是一类高度保守的非编码小分子RNA,经转录后调节细胞的增殖、迁移、分化、凋亡和免疫应答等。miRNAs与心血管疾病发生发展密切相关。心肌缺血后多种miRNA。异常表达,它们在介导心肌缺血再灌注损伤和调控心肌缺血保护环节中起重要作用,可作为诊断缺血再灌注损伤的标志物和潜在治疗靶点。     

Relation between the extent of the myocardial lesion and the state of the coronary bed in acute myocardial infarction

The probability of combined lesion of both ventricles in acute myocardial infarction (AMI) is discussed. In cases of proximal stenosis or occlusion of the right coronary artery, both inferior and right-ventricular (RV) AMI may develop. ECG recordings from the V3R-V6R, V3RIII, V4RIII leads were used for the diagnosis of RV AMI. Elevated ST segment plus the formation of Q waves and a negative T wave in the recordings from these leads indicate RV AMI in the presence of inferior AMI. The extent of myocardial lesion, estimated on the basis of maximum plasma MB CPK activity, is greater in cases of inferior AMI with electrocardiographic signs of RV AMI, as compared to inferior AMI free of such signs.     

血红素氧化合酶系统抗心肌缺血再灌注损伤的研究

血红素氧合酶是血红素分解代谢过程中的限速酶,代谢产物一氧化碳、胆绿素、胆红素对细胞具有保护作用,具有抗氧化应激、抑制炎症反应、抗细胞凋亡和扩张冠状动脉等作用,本文对血红素氧合酶系统抗心肌缺血再灌注损伤的研究进展做一综述。     

Polyamine metabolism in rat myocardial ischemia-reperfusion injury

This study was focused on investigating the involvement of polyamine metabolism in the myocardial ischemia-reperfusion injury (MIRI) in an in vivo rat model. A branch of the descending left coronary artery was occluded for 30 min followed by 2 h, 6 h, 12 h, and 24 h reperfusion. Then the expression of spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) and the concentrations of polyamines were assessed. It was found that the expression of SSAT and ODC were upregulated after reperfusion and the concentrations of spermidine and spermine were significantly decreased, while putrescine concentration was significantly increased. The results suggest that MIRI may cause disturbance of polyamine metabolism, and it may play a critical role in MIRI.     

Glutamine improves myocardial function following ischemia-reperfusion injury

Myocardial ischemia-reperfusion injury is common during cardiac procedures. Glutamine may protect the myocardium by preserving metabolic substrates. Glutamine (0.52 g x kg(-1)) or Ringer's lactate solution (control group) was administered intraperitoneally to 63 Sprague-Dawley rats at 4 or 18 hours prior to experimental ischemia and reperfusion. The hearts were excised and perfused on an isolated working heart model, exposed to global ischemia for 15 min and reperfusion for 1 hour. Left atrial pressure, mean aortic pressure, cardiac flow, coronary flow, and aortic output were measured 15 min before ischemia and every 15 min during reperfusion. There was significantly better cardiac output in the glutamine pretreated groups. Pretreatment at 4 hours before the experiment was superior to pretreatment at 18 hours, with better maintenance of cardiac output and coronary flow. The enhanced protective effect of pretreatment at 4 hours highlights the importance of timing, and suggests a potential clinical benefit.     

褪黑素对心肌缺血再灌注损伤的保护作用

目的　探讨褪黑素增补于停搏液中对缺血再灌注离体鼠心的保护作用。方法　将 2 4只 Wistar大鼠随机分为褪黑素组 (A )和对照组 (B)。离体鼠心在改良的 L angendorff- Neely灌注模型上 30分钟预灌注 ,12 0分钟停搏 ,30分钟再灌注。缺血前及再灌注期间测定血流动力学指标、心肌酶 (包括 CPK、L DH)、心肌超氧化物歧化酶 (SOD)、过氧化脂质 (L PO)含量。电镜观察心肌超微结构。结果　再灌注后 ,A组心功能、心肌超微结构的改善明显优于 B组 ;心肌酶 (CPK,L DH)、过氧化脂质 (L PO)含量显著低于 B组 (P<0 .0 1) ;心肌超氧化物歧化酶 (SOD)含量显著高于 B组 (P<0 .0 1)。结论　褪黑素增补于停搏液中可显著减轻心肌缺血再灌注损伤 ,具有良好的心肌保护作用     

三甲氧苄嗪对心肌缺血/再灌注损伤的保护作用

目的 :探讨三甲氧苄嗪增补于停搏液中对缺血 /再灌注离体鼠心的保护作用。方法 :将 2 4只 Wistar大鼠随机分为三甲氧苄嗪组 （A）和对照组 （B）。离体鼠心在改良的 L angendorff- Neely灌注模型上预灌注 30 min,停搏 12 0min、再灌注 30 min。缺血前及再灌注期间测定血流动力学指标、心肌酶 （CPK,L DH ）、心肌超氧化物歧化酶 （SOD）、过氧化脂质 （L PO）含量、心肌 ATP水平。电镜观察心肌超微结构。结果 :再灌注后 ,A组心功能、心肌超微结构的改善 ,明显优于 B组 ;心肌酶 （CPK ,L DH）、L PO含量显著低于 B组 （P<0 .0 1） ;SOD含量和 ATP水平显著高于 B组（P<0 .0 1）。结论 :三甲氧苄嗪增补于停搏液中可显著减轻心肌缺血 /再灌注损伤 ,具有良好的心肌保护作用     

Mechanisms of flavonoid protection against myocardial ischemia-reperfusion injury

Flavonoids have long been acknowledged for their unique antioxidant properties, and possess other activities that may be relevant to heart ischemia-reperfusion. They may prevent production of oxidants (e.g. by inhibition of xanthine oxidase and chelation of transition metals), inhibit oxidants from attacking cellular targets (e.g. by electron donation and scavenging activities), block propagation of oxidative reactions (by chain-breaking antioxidant activity), and reinforce cellular antioxidant capacity (through sparing effects on other antioxidants and inducing expression of endogenous antioxidants). Flavonoids also possess anti-inflammatory and anti-platelet aggregation effects through inhibiting relevant enzymes and signaling pathways, resulting ultimately in lower oxidant production and better re-establishment of blood in the ischemic zone. Finally, flavonoids are vasodilatory through a variety of mechanisms, one of which is likely interaction with ion channels. These multifaceted activities of flavonoids raise their utility as possible therapeutic interventions to ameliorate ischemia-reperfusion injury.     

The role of neutrophils in myocardial ischemia-reperfusion injury

Reperfusion of ischemic myocardium is necessary to salvage tissue from eventual death. However, reperfusion after even brief periods of ischemia is associated with pathologic changes that represent either an acceleration of processes initiated during ischemia per se, or new pathophysiological changes that were initiated after reperfusion. This 'reperfusion injury' shares many characteristics with inflammatory responses in the myocardium. Neutrophils feature prominently in this inflammatory component of postischemic injury. Ischemia-reperfusion prompts a release of oxygen free radicals, cytokines and other proinflammatory mediators that activate both the neutrophils and the coronary vascular endothelium. Activation of these cell types promotes the expression of adhesion molecules on both the neutrophils and endothelium, which recruits neutrophils to the surface of the endothelium and initiate a specific cascade of cell-cell interactions, leading first to adherence of neutrophils to the vascular endothelium, followed later by transendothelial migration and direct interaction with myocytes. This specific series of events is a prerequisite to the phenotypic expression of reperfusion injury, including endothelial dysfunction, microvascular collapse and blood flow defects, myocardial infarction and apoptosis. Pharmacologic therapy can target the various components in this critical series of events. Effective targets for these pharmacologic agents include: (a) inhibiting the release or accumulation of proinflammatory mediators, (b) altering neutrophil or endothelial cell activation and (c) attenuating adhesion molecule expression on endothelium, neutrophils and myocytes. Monoclonal antibodies to adhesion molecules (P-selectin, L-selectin, CD11, CD18), complement fragments and receptors attenuate neutrophil-mediated injury (vascular injury, infarction), but clinical application may encounter limitations due to antigen-antibody reactions with the peptides. Humanized antibodies and non-peptide agents, such as oligosaccharide analogs to sialyl Lewis, may prove effective in this regard. Both nitric oxide and adenosine exhibit broad spectrum effects against neutrophil-mediated events and, therefore, can intervene at several critical points in the ischemic-reperfusion response, and may offer greater benefit than agents that interdict at a single point in the cascade. The understanding of the molecular processes regulating actions of neutrophils in ischemic-reperfusion injury may be applicable to other clinical situations, such as trauma, shock and organ or tissue (i.e. vascular conduits) transplantation.     

Relation between left ventricular global and regional function and extent of myocardial ischemia in the canine heart

To develop a quantitative relation between the overall severity of acute ischemia and left ventricular global and regional function, two minor axis internal diameters and myocardial wall thickness were determined using ultrasonic crystals in 10 open chest dogs with carotid-left anterior descending artery cannulation. The overall extent of ischemia produced by graded stenosis of the cannulation system was estimated by total myocardial blood flow deficit, calculated using radioactive microspheres and a balloon-reservoir perfusion technique permitting precise separation of ischemic from nonischemic tissue. Although cardiac output and left ventricular stroke work were maintained through chamber enlargement until total myocardial blood flow deficit was about 10%, ejection indexes of left ventricular function decreased progressively with increasing ischemia and correlated inversely with total myocardial blood flow deficit (r = -0.55 to -0.73). Ejection indexes of left ventricular global function correlated directly with regional function in the ischemic zone (r = 0.67 to 0.83), although global function decreased at a far slower rate than regional contraction during progressive coronary stenosis with an ischemic region comprising about 25% of total left ventricular weight. During myocardial ischemia, regional dysfunction resulted in progressive global contractile dysfunction; left ventricular hemodynamic status was maintained until ischemia was severe.     

Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury

Nitrite has emerged as an endogenous signaling molecule with potential therapeutic implications for cardiovascular disease. Steady-state levels of nitrite are derived in part from dietary sources; therefore, we investigated the effects of dietary nitrite and nitrate supplementation and deficiency on NO homeostasis and on the severity of myocardial ischemia-reperfusion (MI/R) injury. Mice fed a standard diet with supplementation of nitrite (50 mg/liter) in their drinking water for 7 days exhibited significantly higher plasma levels of nitrite, exhibited significantly higher myocardial levels of nitrite, nitroso, and nitrosyl–heme, and displayed a 48% reduction in infarct size (Inf) after MI/R. Supplemental nitrate (1 g/liter) in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced Inf. A time course of ischemia-reperfusion revealed that nitrite was consumed during the ischemic phase, with an increase in nitroso/nitrosyl products in the heart. Mice fed a diet deficient in nitrite and nitrate for 7 days exhibited significantly diminished plasma and heart levels of nitrite and NO metabolites and a 59% increase in Inf after MI/R. Supplementation of nitrite in the drinking water for 7 days reversed the effects of nitrite deficiency. These data demonstrate the significant influence of dietary nitrite and nitrate intake on the maintenance of steady-state tissue nitrite/nitroso levels and illustrate the consequences of nitrite deficiency on the pathophysiology of MI/R injury. Therefore, nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a treatment modality for cardiovascular disease.     

鸢尾素对缺血再灌注心肌铁死亡的抑制作用

目的 建立小鼠心肌缺血再灌注（MI/R）损伤模型,探讨鸢尾素（irisin）能否抑制心肌铁死亡进而发挥心肌保护作用。 方法 将80只5周龄健康雄性C57小鼠随机分为正常对照组（40只）和运动训练组（40只）。运动组完成训练后进一步将两组小鼠分为假手术组和MI/R组（每组20只）。采用小鼠急性MI/R在体模型(缺血30 min,再灌注24 h) 于再灌注后取心肌组织,检测各组血清及组织中irisin水平、铁死亡相关信号表达、心肌梗死面积和整体心脏功能。在细胞学实验中,采用H9c2心肌细胞建立缺氧/复氧（H/R）模型并给予irisin处理后检测铁死亡相关信号表达情况。 结果 铁死亡抑制剂ferrostatin-1可显著减小MI/R心肌梗死面积,降低MI/R心肌中铁死亡标志物Ptgs2 mRNA和丙二醛（MDA）水平,提示心肌铁死亡是MI/R心肌损伤的重要部分。与对照组相比,有氧运动训练可有效提高骨骼肌和心肌中的irisin水平（P<0.05）。运动组MI/R心肌的铁死亡程度被显著抑制,心肌Ptgs2 mRNA、MDA和脂质过氧化程度均显著降低（P<0.05）,心功能显著改善（P<0.05）。外源性补充irisin可有效提高MI/R心肌中GPX4水平而抑制心肌铁死亡程度,减小心肌梗死面积（P<0.05）。细胞学实验发现采用siRNA抑制H9c2细胞整合素αV/β5受体可有效阻断irisin对铁死亡的抑制作用。 结论 鸢尾素通过整合素αV/β5受体-GPX4信号途径抑制MI/R心肌铁死亡。有氧运动训练可通过提高内源性irisin水平实现心肌保护作用。