一氧化氮在心肌细胞凋亡中的作用

作者综述了一氧化氮 （NO）对心肌细胞凋亡的作用机制。NO对心肌细胞的作用有双重性 :既是组织损伤的中间介质 ,又在心肌缺血 /再灌注损伤中有保护心肌作用。它可通过氧化应激反应 ,作用于心肌细胞的一些蛋白质、酶类、细胞因子以及胞液的钙超载等途径来影响心肌细胞凋亡     

活血化瘀中药保护心肌缺血-再灌注损伤研究进展

通过对近年来活血化瘀中药保护心肌缺血-再灌注损伤方面的基础和临床研究的文献总结,发现其保护作用机制具有多靶点、多层面的特点,主要从清除自由基、拮抗钙超载、抑制心肌细胞凋亡、保护血管内皮功能、改善微循环和血流动力学以及心肌缺血预保护等方面发挥活血化瘀中药保护心肌缺血-再灌注损伤的研究进展作用.     

锌对心肌保护作用机理的探讨

应用电镜、电子示踪技术和立体计量测试法，从形态学上观察异丙基肾上腺素对心肌膜系统的影响及锌的保护作用，同时应用标准玻璃微电极技术和微机实时分析方法，研究异丙基肾上腺素致心肌损伤及锌对心肌保护作用的机理。实验结果表明：异丙基肾上腺素可引起心肌细胞膜系统损伤，此时心肌细胞的去极化和复极化过程均发生改变；经锌前处理后，心肌损伤程度明显减轻，心肌细胞的复极化过程得到明显改善。锌对心肌的保护作用，主要是通过阻断心肌细胞膜慢通道、减少平台期钙离子内流、防止细胞内钙超载来实现。     

从钙超载角度探讨通脉养心丸心肌保护作用的机制

目的从抑制钙超载的角度探讨通脉养心丸抗细胞凋亡保护心肌的作用机制。方法采用大鼠心肌细胞原代培养方法获得正常心肌细胞并建立缺氧损伤细胞模型,采用FLIPR Calcium 4试剂盒检测药物对胞浆内钙离子浓度变化的影响;Annexin V/PI双染法检测心肌细胞总凋亡率。结果缺氧损伤组心肌细胞胞浆内钙离子浓度显著升高(P<0.01),通脉养心丸各剂量组变化不显著;再次加药后,通脉养心丸各剂量组胞浆内钙离子浓度均显著低于缺氧损伤组(P<0.01)。缺氧损伤组心肌细胞凋亡率显著升高(P<0.01),通脉养心丸4 g/kg、8 g/kg剂量组可显著降低心肌细胞凋亡率(P<0.01)。结论抑制心肌细胞钙超载是通脉养心丸抗心肌细胞凋亡保护心肌的作用机制之一。     

地奥心血康对实验性心肌损伤的保护作用及其机理

大鼠皮下注射异丙肾上腺素(ISO)造成心肌损伤模型,其心肌含水量、血清肌酸激酶(CK)、乳酸脱氢酶(LDH)、心肌钙含量、丙二醛含量及心肌病理学损伤程度分级均有显著增加(均P<0.01).如同时应用地奥心血康(DK;20mg/kg,ip),则上述指标比不用DK者分别减少2.6%、46.6%、60.9%、37.2%和30.5%,病理分级也显著降低(均P<0.05).表明DK对缺血损伤心肌具有明显的保护作用.其机理主要为防止心肌细胞钙超载及减轻氧自由基损伤.     

脱氢紫堇碱在心肌细胞钙调控中的作用

背景已有动物实验表明脱氢紫堇碱(DHC)可能通过阻止心肌细胞内钙超载,提高心肌细胞的自我保护作用,但还没有相关实验阐明DHC调控心肌细胞保护的分子机制.目的 探讨DHC对心肌细胞内Ca2+超负荷及Ca2+调控相关蛋白的表达变化.方法 采用逆转录聚合酶链反应(RT-PCR)方法 对心肌细胞Ca2+调控相关蛋白,包括钙三磷...     

曲美他嗪的心肌保护机制及其在心血管疾病中的应用进展

缺血心肌的代谢治疗逐渐成为国内外学者研究的热点,曲美他嗪是近几年来普遍受到人们关注的抗代谢药物,它可以在不增加心肌供氧的前提下,通过改变心肌细胞的有氧代谢途径,提高对氧的利用效率,优化心肌细胞的能量代谢,减轻细胞内酸中毒、钙超载,保护线粒体功能,在细胞水平发挥保护作用,使心肌缺血症状得以缓解,却不对血流动力学产生任何负面影响。目前被广泛应用于缺血性心脏病、介入治疗、外科手术,以及其他心血管疾病所导致的心肌损伤等领域。     

中药保护心肌缺血损伤的非循环机制研究进展

中药保护心肌缺血损伤的非循环机制主要包括抑制心肌细胞凋亡、心肌缺血预处理、改善心肌超微结构、心肌酶和免疫功能调节.中药可通过非循环机制增强心肌细胞内源性抗损伤能力,内源性调控保护可能是更有效的心肌保护策略,体现了中西医结合治疗心血管疾病能从整体出发多层面、多靶点发挥作用的优势.     

钠钙交换蛋白与心肌保护

钠钙交换蛋白在心肌细胞内Ca2 浓度的调节中起着重要作用。在心肌缺血再灌注损伤中,钠钙交换蛋白被认为是钙超载的主要路径,从而导致心肌细胞的机械和电活动功能障碍。钠钙交换蛋白抑制剂benzyloxyphenyl衍生物(KB-R7943、SEA0400和SN-6)能特异地、有效地抑制钠钙交换蛋白的Ca2 内流模式,提供良好的心肌保护作用。     

益气温阳法对大鼠心肌缺血-再灌注性心律失常钙超载及Ca^2＋-ATPase的影响

目的 研究益气温阳中药复方对大鼠心肌缺血-再灌注心律失常的防治作用,通过检测各项指标,探讨其可能的作用机制.方法 以左冠状动脉前降支结扎后复灌大鼠为模型,测定假手术组、模型组、普罗帕酮(心律平)对照组、中药治疗组心肌钙离子含量以及 Ca2+-ATPase活性.结果 益气温阳中药复方能防止缺血再灌注性心律失常的发生,减轻心肌组织钙超载,减轻Ca2+-ATPase活性下降.结论 益气温阳中药复方对大鼠心肌缺血再灌注心律失常具有明显保护作用,主要与减轻心肌组织钙超载,增强Ca2+-ATPase活性有关.     

Mechanisms of cardiac hypertrophy and injury--possible role of protein kinase C activation.

To examine the molecular mechanisms by which mechanical stimuli induced cardiac hypertrophy and injury, we cultured rat neonatal cardiocytes in deformable dishes and imposed an in vitro mechanical load by stretching the adherent cells. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos. Marked accumulation of c-fos mRNA followed increases in intracellular Na+ and protein kinase C activation. The accumulation of c-fos mRNA by cardiocyte stretching was suppressed by protein kinase C inhibitors but not by stretch channel blockers. Moreover, myocyte stretching increased inositol phosphate levels, and activation of protein kinase C by phorbolesters stumulated the expression of c-fos. We also examined TGF beta expression in the heart. TGF beta is known to be stimulated by protein kinase C activation, and the mRNA level of TGF beta was increased in in vivo heart by pressure overload. Furthermore, collagen synthesis was stimulated by TGF beta in cultured fibroblasts from hearts. These findings suggest that hemodynamic overload may stimulate cardiac hypertrophy and induce cardiac injury (fibrosis) through protein kinase C activation.     

钙通道阻滞剂改善内质网应激抑制压力过负荷高血压大鼠的心肌重构

目的:研究在压力过负荷应激状态下钙通道阻滞剂拉西地平对内质网应激（endoplasmic reticulum stress,ERS）分子钙网蛋白（calreticulin,CRT）和细胞凋亡效应分子-12(caspase-12)在大鼠心肌组织中的表达及对心肌重构的影响。方法: 将30只雄性Sprague-Dawly(SD)大鼠随机分为3组,即假手术组(Sham组)、腹主动脉缩窄组（TAC组）及TAC＋拉西地平干预组（简称拉西地平组）,每组10只。通过颈动脉插管测定各组大鼠的血流动力学,心脏超声心动图检查左心室的形态结构。采用免疫组化染色法检测大鼠心肌中CRT及caspase-12蛋白的表达水平,TUNEL荧光染色法检测心肌细胞的凋亡率。结果: 与Sham组相比较,TAC组大鼠的平均动脉压(MAP)、室间隔厚度(IVST)、左室后壁厚度(LVPWT)、左室质量指数(LVWI)、CRT和caspase-12蛋白表达水平及心肌细胞的凋亡率比较,均有显著升高(P<0.01)。拉西地平组大鼠MAP、IVST、LVPWT、LVWI、CRT和caspase-12蛋白的表达水平及心肌细胞的凋亡率较TAC组明显下降(P<0.05)。结论: 内质网应激可能参与了压力过负荷高血压大鼠心肌重构的过程。钙通道阻滞剂拉西地平可能通过降低CRT及caspase-12的表达及减少心肌细胞的凋亡干预ERS介导的压力负荷所致高血压大鼠心肌肥厚的信号通路,从而通过改善内质网应激发挥对心脏的保护作用。     

Myocardial ischemia-reperfusion injury and melatonin]

It is believed that myocardial ischemia-reperfusion injury is related to increased free radical generated and intracellular calcium overload especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger, antioxidant and can inhibit the intracellular calcium overload. In this review, we have summarized the fundamental of cardiac ischemia-reperfusion injury and the effects of melatonin on myocardial damage that related to cardiac ischemia-reperfusion injury. The total antioxidant capacity of human serum is related to melatonin levels. Incidence of sudden cardiac death is high in the morning hours. It has been shown that melatonin levels are significantly low at these times and patients with coronary heart disease have lower than normal individuals. These findings thought that melatonin would be valuable to test in clinical trials for prevention of possible ischemia-reperfusion-induced injury, especially life threatening arrhythmias and infarct size, effecting life quality, associated with thrombolysis, angioplasty, coronary artery spasm or coronary bypass surgery.     

Inhibition des späten Natriumeinstroms (INa,late) als neuartige kardioprotektive Therapieoption

Over the last few years, it has been shown that the late sodium current (I_Na,late) mediated by voltage-gated cardiac sodium channels plays an important role in the pathophysiology of myocardial ischemia. A rise in I_Na,late increases the intracellular sodium concentration. In consequence, the myocyte eliminates sodium ions through the sarcolemmal Na/Ca exchanger (NCX), leading to calcium overload and hence contractile dysfunction. By specifically inhibiting I_Na,late, this pathological cascade can be interrupted by improving the intracellular sodium concentration and hence the NCX-dependent calcium overload. Experimental data suggest that inhibition of I_Na,late decreases infarct size and improves left ventricular function after acute ischemia and during chronic heart failure. As a potent inhibitor of I_Na,late, ranolazine improves angina pectoris symptoms without changing blood pressure or heart rate. New clinical studies even point to beneficial antiarrhythmic effects. This review focuses on relevant pathophysiological concepts in which I_Na,late plays a role and summarizes the latest basic and clinical data.     

Therapeutic potential of novel Na+-Ca2+ exchange inhibitors in attenuating ischemia-reperfusion injury

The cardiac Na+-Ca2+ exchanger (NCX) plays an essential role in regulating Ca2+ under physiological and pathophysiological conditions. In its forward mode of operation, which predominates under physiological conditions, it extrudes the Ca2+ that enters the cardiac myocyte on a beat-to-beat basis. During ischemia and reperfusion, increased intracellular Na+ leads to a decrease in Ca2+ efflux and enhanced Ca2+ influx via the NCX, potentially leading to Ca2+ overload, which is one of the major pathophysiological mechanisms for ischemia-reperfusion injury. Novel NCX inhibitors discovered in recent years have shown great promise in attenuating ischemia-reperfusion injury.     

Calcium movements in relation to heart function

Summary It is widely recognized that calcium is of singular importance in the viability of the myocardial cell, nonetheless little is known concerning the precise nature of the action of calcium in myocardium as to how it maintains the life of the cell and how it may dictate the death of the cell. However, recent advances in research involved with the study of calcium movement in the heart have been highly valuable for the formulation of new concepts with respect to the physiological and pathological aspects of calcium metabolism in the myocardium. It is becoming clear that calcium movements are closely related to cardiac electrophysiological events, contractile function, membrane integrity and energy metabolism. In particular, a novel theory involving phosphatidylinositol turnover and Ca²⁺-dependent ATPase activation has been advanced regarding the mechanism and control of calcium entry into the cardiac cell upon excitation. Alterations in the regulation of calcium metabolism through the interaction of a number of separate, elements may affect calcium distribution in the cell and thereby may change cardiac function and metabolism. The part calcium plays in the genesis of pathological states in the myocardium is discussed in the light of research employing various experimental protocols. Intracellular calcium overload and deficiency are postulated to contribute to cardiac contractile failure and cell death through a number of distinct mechanisms. It is now a real challenge to understand the precise nature of processes associated with the occurrence of intracellular calcium overload or intracellular calcium deficiency in order to achieve proper management of cardiac disorders.Supported by a grant from the Medical Research Council of Canada.     

Clinical and experimental aspects of myocardial stunning.

Although the mechanisms involved in stunning remain incompletely defined, it appears that intracellular calcium overload, sarcoplasmic reticulum dysfunction, and the generation of OFR are important components of post-ischemic myocyte dysfunction. It is likely that a variety of mechanisms, some possibly remaining to be elucidated, are operative in the pathogenesis of stunning, and that the contribution of a particular process may be influenced by the model and the method of inducing ischemia. Myocardial stunning has been shown to be prevalent in patients with diverse cardiac diseases. Small clinical trials have suggested that electrocardiography, echocardiography, and radionuclide imaging techniques may be useful in identifying patients with stunned myocardium. In patients with depressed cardiac performance due to stunning, therapy with inotropic agents may recruit the viable but injured myocardium to contract and improve cardiac output in the short term. An important issue that will be addressed over the next decade is whether aggressive therapy aimed at reducing myocardial stunning in stable patients should be attempted. Some authorities have suggested that stunning may represent an adaptive response to limit reperfusion injury, and that interfering with this response may not be beneficial in the long term. Further investigation into the cellular and molecular basis of ischemic injury should provide insight into these and other important aspects of myocardial stunning. Methods of attenuating postischemic ventricular dysfunction that appear convincing in the research laboratory may not translate to clinical benefit when applied to humans.     

Molecular oxygen: friend and foe. The role of the oxygen free radical system in the calcium paradox, the oxygen paradox and ischemia/reperfusion injury

We strongly support the original intriguing hypothesis of Hearse et al. that the oxygen paradox and the calcium paradox are facets of the same problem. We would propose that the major similarity is a final common pathway leading to intracellular calcium overload and the sequelae of the resultant increase in intracellular calcium. In addition, we would propose that the oxygen paradox and ischemic/reperfusion injury are also facets of the same problem with the major similarity being the reintroduction of molecular oxygen to a previously hypoxic myocardium. Finally, we would suggest that the common pathway leading to intracellular calcium overload in the oxygen paradox and ischemic/reperfusion injury and to a lesser extent the calcium paradox involves the generation of oxygen free radicals. The source of oxygen free radical generation in the calcium paradox is perhaps less obvious than in the oxygen paradox. It is proposed that during calcium-free perfusion, calcium is leached from the plasmalemma of the myocyte. There is a resulting increase in membrane fluidity. Within the plasmalemma are a number of calcium sensitive phospholipases. Upon reperfusion with a calcium replete medium, calcium could pool around these membrane bound phospholipases initiating a chain reaction of lipid peroxidation which actually is perpetuated by free radical generation (Equations 5A-5C). Lipid peroxidation opens channels within the plasmalemma rendering a 'leaky' sarcolemma. It is through these channels that calcium could flow down its concentration gradient into the cell. The increased calcium accumulation at the mitochondria would lead to an uncoupling of oxidative phosphorylation. With depleted energy stores, the mitochondria and sarcoplasmic reticulum no longer serve as calcium sinks. This would contribute to the calcium overload seen upon reperfusion. The role of oxygen free radical production would appear to occur during the hypoxic phase of the oxygen paradox and the ischemic phase of ischemic/reperfusion injury and during the reoxygenation/reperfusion phases. With the onset of hypoxia and/or myocardial ischemia there is an increase in reducing equivalents, disturbance and dissociation of intramitochondrial electron transport and release of ubisemiquinone, flavoproteins and superoxide radicals. The increase in reducing equivalents includes NADPH and, in ischemia, catecholamines, hypoxanthine and an increase on xanthine oxidase activity. All of these substrates are capable of participating in free radical production. This increase in free radical production in ischemic tissue is enhanced by acidosis which in the ischemic and hypoxic myocardium approaches pH 6.0-6.4.(ABSTRACT TRUNCATED AT 400 WORDS)     

黄芪苷Ⅳ对心肌细胞氧化损伤的保护作用

目的研究黄芪苷Ⅳ对阿霉素所致心肌细胞损伤的保护作用。方法以原代培养乳鼠心肌细胞建立损伤模型。实验分3组。正常对照组;模型组:阿霉素分别为0.5、1.0mg/L与乳鼠心肌细胞共同培养;黄芪苷Ⅳ组:在加入阿霉素前1h分别给予黄芪苷Ⅳ10、20mg/L,然后加入与模型组相同浓度的阿霉素共同培养。观察心肌细胞四甲基偶氮唑盐(MTT)代谢率、丙二醛(MDA)含量及一氧化氮合酶(NOS)活性的变化,并测定心肌细胞内的游离钙离子浓度。结果阿霉素组心肌细胞的MTT代谢率显著降低(P<0.01),MDA含量增加(P<0.05),NOS活性升高(P<0.05),[Ca2+]i升高(P<0.01)。黄芪苷Ⅳ可使阿霉素损伤的心肌细胞MTT代谢率提高,MDA含量减少(P<0.05),NOS活性降低(P<0.05),[Ca2+]i降低(P<0.01)。结论黄芪苷Ⅳ对受损伤的心肌细胞具有明显的保护作用。     

Beta1-adrenergic receptors promote focal adhesion signaling downregulation and myocyte apoptosis in acute volume overload

Numerous studies demonstrated increased expression of extracellular matrix (ECM) proteins and activation of focal adhesion (FA) signaling pathways in models of pressure overload-induced cardiac hypertrophy. However, little is known about FA signaling in response to volume overload where cardiac hypertrophy is associated with ECM loss. This study examines the role of beta1-adrenergic receptors (β(1)-ARs) in FA signaling changes and myocyte apoptosis induced during acute hemodynamic stress of volume overload. Rats with eccentric cardiac hypertrophy induced after aorto-caval fistula (ACF) develop reduced interstitial collagen content and decreased tyrosine phosphorylation of key FA signaling molecules FAK, Pyk(2) and paxillin along with an increase in cardiac myocyte apoptosis. ACF also increased activation of PTEN, a dual lipid and protein phosphatase, and its interaction with FA proteins. β(1)-AR blockade (extended-release of metoprolol succinate, 100mg QD) markedly attenuated PTEN activation, restored FA signaling and reduced myocyte apoptosis induced by ACF at 2days, but failed to reduce interstitial collagen loss and left ventricular dilatation. Treating cultured myocytes with β(1)-AR agonists or adenoviral expression of β(1)-ARs caused PTEN activation and interaction with FA proteins, thus leading to FA signaling downregulation and myocyte apoptosis. Adenoviral-mediated expression of a catalytically inactive PTEN mutant or wild-type FAK restored FA signaling downregulation and attenuated myocyte apoptosis induced by β(1)-ARs. Collectively, these data show that β(1)-AR stimulation in response to ACF induces FA signaling downregulation through an ECM-independent mechanism. This effect involves PTEN activation and may contribute to adverse cardiac remodeling and function in the course of volume overload.