医学论文翻译

In this study, a transient mechanical stretch of the left ventricle significantly reduced infarct size in rat heart. AMPK phosphorylation was enhanced by mechanical stretch in both ex vivo and in vivo (ACS) heart model and was sup-pressed by Gd3＋. Mechanical stretch -induced cardiopro-tection was blocked by Gd3＋and Compound C. AICAR, an AMPK activator, instead of mechanical stretch protected heart from I/R injury. These results suggest that AMPK plays an important role in the SIC, and this role might be regulated by SACs.

In this study, there were no significant differences in base-line functional parameters, including HR, LVEDP, SP, and CBF, among all groups prior to imparting sustained ische-mia (Fig. 2C and Fig. 5C). Therefore, SIC could not be as-

Fig. 5. Effects of stretch precon-ditioning on the infarct size and the functional recovery of in vivo rat hearts. (A) Infarct size was measured using TTC staining after 30 minutes ischemia and 1 hour reperfusion and (B) normalized infarct size was cal-cula ted and compared. All data are means±SEM of N≥6 in each experi-mental group. *p＜0.05 compared with I/R Con group. I/R Con, ischemia-reperfusion control; ACS Sham, sham-operated hearts; ACS, aorto -caval shunt. (C) Functional recovery of in vivo stretched rat hearts. Cardiac function was evaluated in terms of 4 parameters; cardiac functional re-covery, Left ventricular end-diastolic pressure (LVEDP), heart rate, and coronary blood flow. The changes of 4 parameters were traced during 60 minutes post-ischemic reperfusion period. All data are means±SEM of N≥6 in each experimental group. *p＜0.05 compared with control group. ●, ischemia-reperfusion control; ○, Sham; ▼, 10 minutes ACS; ▽, 20 minutes ACS; ACS, aorto-caval shunt.

cribed to stretch induced-hemodynamic changes. Mechanical stretch in the heart can be produced by in-creasing the left ventricular wall tension expressed as an increase in LVEDP. In this study, the left ventricular wall tension was increased by in vivo volume overload using an ACS rat heart model. Huang and his coworkers [32] demon-strated two episodes of brief pressure overload of the left ventricle by transverse aortic constriction significantly re-duced myocardial infarct size. t Although the left ventricular systolic pressure was raised 50% above the baseline and the protection of pressure overload was abolished by block-ing stretch-activated ion channels, he study did not pro-vide any evidence of increase in the length of left ven-tricular segment. In the present study, increase in LVEDP seen in the ACS rats (Fig. 4A) indicates that volume over-load adequately increased diastolic wall stress and stretch-ed left ventricular end diastolic length.

On the other hand, there is a possibility that brief volume overload might cause changes in myocardial blood flow and induce transient ischemic stress in the heart. In the present study, myocardial lactate content at baseline and after 30 minutes of mechanical stretch was negligible as compared to the contents after 10 minutes ischemia (Table 1). Overall, there was no evidence of myocardial ischemia during stretch pretreatment and these results suggested that the effect of endocardial ischemia did not seem to play an im-portant role in cardioprotection of mechanical stretch.

Several non-ischemic stimuli can also precondition the myocardium, including pharmacological administration and myocardial stretching. In fact, it was shown that isolated hearts stretched by a transient increase in LVEDP, offered similar protection as classical ischemic preconditioning [7-10]. Clearly, acute volume overload significantly dilated the myocardium, and those hearts that underwent this stretching during the treatment period developed sig-nificantly smaller infarcts after a subsequent coronary ar-tery occlusion for 30 minutes than the control hearts. In this study, the protective effect of stretch was confirmed in isolated heart and in vivo volume overload heart. In ac-cordance with previous reports, SPC renders cardiopro-tection against I/R injury in rats as evidenced by improving cardiac functional recovery during the reperfusion period and resulting reduction in infarct size. Although the exact mechanism is still not known, the protection was abolished by administration of Gd3＋, an inhibitor of SACs. Therefore, the protective effect of SPC might be related to activation of SACs.

Mechanical stretch can activate cellular signal trans-duction pathways, such as the JNK, a group of MAPK, PKC, and JAK/STAT pathway [9-11]. In addition, stretch is also known to activate the AMP-activated protein kinase (AMPK) in muscle cells [12,13]. AMPK is a serine-threonine kinase, which is emerging as an important regulator of di-verse cellular pathways in regulating whole-body energy metabolism. AMPK is responsible for the switching on of the catabolic pathways, stimulating the oxidation of FFAs and enhancing glucose uptake and glycolysis that produce ATP while alleviating the ATP-consuming processes [18-20]. Recently, it has been reported that AMPK prevents ische-mic injury in the hearts [21,22], and that IPC and heat shock induced protection occurs via AMPK activation in liv-er and heart [16,23,24]. Furthermore, AICAR affords the protection against I/R injury [25,26]. Therefore, AMPK has emerged as a new pathway that plays an important pro-tective role in the process of cardioprotection. In the present study, SPC-activated AMPK precede the sustained ische-mia relative to control (Fig. 3A). Activity of AMPK as meas-ured by the phosphorylation of ACC was inhibited by Compound C, which was accompanied by abrogation of SIC (Fig. 2, 3). Moreover, myocardial stretch time- dependently increased AMPK phosphorylation in vivo. In accordance with the results of AMPK activity, 20 minutes of ACS showed a significant cardioprotection, while 10 minutes of ACS did not (Fig. 5). These results suggested that my-ocardial stretch can activate AMPK and that AMPK plays an important role in SIC.

AMPK activation could increase energy production dur-ing ischemia. However, it augments fatty acid oxidation during ischemia/reperfusion when fatty acid level is high. Studies using isolated rat hearts perfused with glucose and fatty acids suggested that AMPK-dependent acceleration of fatty acid oxidation occurs at the expense of

glucose oxida-tion, and has the potential to be detrimental to the ischemic heart [33]. Since fatty acids were not included in buffer as an energy source in this study, it is possible that untoward effects of AMPK activation that would occur in hearts in situ may have been masked. The question of whether AMPK activation is an ally or enemy to the ischaemic heart remains to be completely elucidated. Long-term experi-ments in intact animals and in vivo ischaemia-reperfusion models are necessary to clearly define whether AMPK acti-vation is an ally or enemy to the ischaemic heart.

SACs and their relationship to AMPK activation were al-so studied; Gysembergh et al. [6] indicated that stretch can provide cardioprotection by PKC which is regulated via SACs. Nishino et al. [24] have shown that PKC inhibitors abolished AMPK activation by ischemic episodes, suggest-ing that AMPK might be activated by IPC in a PKC-de-pendent manner. Another candidate is LKB1 which has been shown recently to be the upstream kinase phosphor-ylating AMPK [34]. LKB1 has a fundamental role in cell cycle regulation protein synthesis, suggesting involvement in a number of disorders including cardiac hypertrophy, cancer, and atherosclerosis. AMPK is activated by many stress conditions that deplete cellular ATP and the in-creased ratio of AMP to ATP seems to render AMPK a bet-ter substrate for LKB1. It has been reported that the ratio of AMP/ATP increased 5 times above control which was as-sociated with increased AMPK activity in overload-induced hypertrophied hearts [17]. Together, it is plausible to as-sume that mechanical stress might cause a fast, transient depletion of intracellular ATP storage, which changes the AMP- to-ATP ratio so that AMPK serves as a better sub-strate for an activated AMPK kinase, namely LKB1. Further studies are necessary to examine whether SACs can medi-ate AMPK by PKC or LKB1 in process of SIC.

Despite the fact that SPC is as potent as IPC, we are unable to apply SPC for patient treatments per se. However, SPC may be an important mechanism protecting car-diomyocytes from necrosis and apoptosis at the time of sud-den pressure overload, for example, during malignant hy-pertension, and at the times of acute volume overload as in acute aortic regurgitation. SPC is an obvious tool for analysis of myocyte protection mechanism and future re-search promises to elucidate the molecular mechanisms re-sponsible for AMPK activation, novel downstream AMPK targets, and the therapeutic potential of targeting AMPK for the development of new therapeutic strategies for treat-ment of ischemic heart disease.

In conclusion, this study suggests that SPC can induce the cardioprotection against I/R injury, and SIC mediates this action by activation of AMPK with possible association with SACs.

翻译：在这项研究中,一个瞬态机械拉伸的左心室显著降低大鼠心脏梗塞面积。AMPK磷酸化是通过在两个体外和体内(ACS)心脏模型的机械拉伸而增强（提高）,通过Gd3呷压+刺激兴奋。机械拉伸引起cardiopro-tection被Gd3 +和化合物C阻塞。AICAR,一个AMPK催化剂,代替了机械拉伸来保护心脏免于I/ R损伤。这些结果表明AMPK在SIC中扮演了重要的角色,而且这个角色可能被SACs管理。

在这项研究中,在优先传授可持续的inche-mia的所有小组中(图2 c和图5 c)，基线功能参数没有显著差异,包括HR、LVEDP,SP,CBF。Therefore, SIC could not be as-（这个句子不完整）

牵张预适应对心肌梗死面积在大鼠体内的心脏功能恢复的影响。（A)在缺血30分钟和1小时再灌注之后，采用用TTC染色法测定心肌梗死面积。（B）归梗死面积可计算出并进行比较。在每个实验组所有数据均为平均值±SEM的N≥6。*与I / R Con组相比P <0.05。I /?体质，缺血再灌注控制；ACS深，假手术组的心; ACS，腹主动脉，下腔静脉分流术。（C）在体内拉伸大鼠心脏功能恢复。4个参数进行了评估心脏功能;心功能重新恢复。左室舒张末压（LVEDP）：心跳率，及冠状动脉血流量。在60分钟后缺血再灌注期间，对4个参数的变化进行追踪。在每个实验组中所有的数据是平均值±SEM的N≥6。与对照组相比，* P<0.05，..●缺血再灌注损伤控制;○深水▼，10分钟ACS;▽，20分钟ACS，ACS，腹主动脉，下腔静脉分流术

cribed伸展引起的血流动力学改变。可以通过机械拉伸的心脏在压痕LVEDP 的增加表示为左室壁张力。在这项研究中，通过体内容量超负荷使用ACS大鼠心脏模型，左心室壁的张力增加了。黄和他的同事们[32]表明简短压力负荷的横向主动脉狭窄大大降低心肌梗死面积的左心室的两集。虽然左心室收缩压提高50％以上的基线和压力过载的保护块牵张激活的离子通道被废除，但是他的研究没有提供任何左心室段的长度增加的证据。在本研究中，增加LVEDP出现在ACS大鼠组（图4A）表示，适度增加量过载舒张期室壁压力和拉伸的左心室舒张末期长度。

另一方面，有一种可能性，即简要容量负荷可能会导致在心脏心肌血流量的变化，并引起短暂性脑缺血胁迫。在本研究中，与缺血后10分钟（表1）的内容相比，在基线和机械拉伸的后30分钟的心肌乳酸含量是可以忽略不计的。总体而言，在拉伸预处理过程中没有心肌缺血的证据，这些结果表明，心内膜缺血的影响似乎没有在心肌机械牵张方面起着重要的作用。

一些非缺血性刺激也可以是先决条件，包括药物管理和心肌拉伸心肌。事实

上，结果表明，LVEDP的一个短暂增加的离体心脏拉伸，提供了类似的保护，经典缺血预处理[7-10]。显然，急性容量负荷增加明显扩张心肌，在后续的冠状动脉ar-tery闭塞30分钟后，那些在治疗期间进行拉伸的心出现了比对照心更小的梗塞。在这项研究中，拉伸的保护作用被证实在离体心脏和生物体内容量超负荷心。按照以前的报告中，SPC使cardiopro对I / R损伤作用的保护，证明了再灌注期间改善心功能的恢复和导致心肌梗死面积减少。虽然确切的机制尚不清楚,但这种保护通过管理Gd3 +,一种抑制剂囊而被取消。因此，SPC 的保护作用可能与活化的囊有关。

机械拉伸可以激活细胞内信号转导途径，如JNK，一组MAPK，PKC和JAK/ STAT信号通路[9-11]。此外，众所周知的是拉伸在肌肉细胞中激活AMP活化的蛋白激酶（AMPK）[12,13]。AMPK是一种丝氨酸- 苏氨酸激酶，它是一种调节整个机体能量代谢的新兴的多样化细胞通路中的重要调节器。AMPK负责代谢途径的开关，包括刺激游离脂肪酸，提高葡萄糖的摄取和产生ATP而缓解ATP 消费过程的糖酵解作用[18?20]。最近，有报道称，AMPK防止缺血再灌注损伤的心脏[21,22]，而通过AMPK激活IPC和热休克引起的保护发生在肝脏和心脏[16,23,24]。此外，AICAR提供了对I/ R损伤的保护。因此，AMPK又出现了一个新的途径，在心脏保护作用的过程中，起着重要的保护作用。本研究中，在持续缺血相对能控制之前SPC激活AMPK。通过ACC的磷酸化测量AMPK活性被化合物C抑制，化合物C同时伴随着废除碳化硅(图2、3)。此外，心肌拉伸时间依赖性地增加体内的AMPK磷酸化。按照AMPK活性的结果，20分钟的ACS表现出明显的心脏保护作用，而10分钟的ACS没有（图5）。这些结果表明，心肌拉伸可以激活AMPK，AMPK在SIC中起着重要的作用。

在缺血过程中，AMPK的激活会增加能源生产。但是，当脂肪酸水平高的时候，它在缺血/再灌注期间可以增强脂肪酸氧化。使用灌注葡萄糖和脂肪酸的离体大鼠心脏的研究表明，AMPK依赖加速度脂肪酸氧化是以葡萄糖氧化为代价，并且有可能有损于缺血性心脏病[33]。因为脂肪酸并不包括在这项研究中的缓冲区作为能源，所以发生在原位心脏的AMPK活化的不良反应可能被掩盖。AMPK激活对于缺血性心脏是盟友还是敌人的问题仍有待完全阐明。在完整的动物体内缺血再灌注模型的长期实验中，有必要明确界定AMPK激活是缺血性心

脏的盟友还是敌人。

此外研究了囊和它们与AMPK 激活的关系；Gysembergh等人的研究表明，拉伸可以通过PKC提供心脏保护作用,PKC是通过囊监管。Nishino等人表明，PKC抑制剂通过缺血发作取消了AMPK激活，AMPK可能在PKC依赖的方式中被IPC激活。另一位候选人是LKB1，最近它已被证明是AMPK的上游激酶磷酸化[34]。LKB1在细胞周期调控蛋白的合成方面有着根本的作用，这表明一些疾病包括心肌肥厚、癌症和动脉粥样硬化的参与。激活AMPK有许多应力条件,耗尽细胞ATP和加大的ATP、AMP比率似乎使AMPK成为LKB1一个更好的基板。有报道称，AMP/ ATP的比例在控制范围内增加了5倍，这与超负荷引起的心肌肥厚心脏的AMPK活性增加有关[17]。在一起，这是合理的假设，机械应力，可能会导致细胞内ATP存储快速、瞬态耗尽，改变了AMP-ATP比例，使AMPK激活AMPK激酶，LKB1作为一个更好的基板。进一步的研究是必要的,以检查囊是否可以调解AMPK PKC或SIC过程中的LKB1。

尽管SPC如IPC一样有效，但是我们无法把SPC应用到对病人的治疗本身。然而，SPC可能是在突然压力过载的时候保护心肌细胞坏死和凋亡的一种重要机制，例如，在恶性高血压和急性主动脉瓣关闭不全的急性容量超负荷的时候。SPC 是明显的心肌细胞保护机制分析工具，未来的研究有望阐明负责AMPK激活、新型的的下游AMPK目标和为治疗缺血性心脏疾病针对AMPK发展新的治疗策略的治疗潜力的分子机制。

总之，这项研究表明，SPC可产生抗心肌I/ R损伤的心脏保护作用，SIC 通过与囊有可能联系的AMPK的激活来调解这一行为