联合应用芬太尼后处理和远隔缺血后处理对大鼠在体心肌缺血—再灌注损伤的保护作用及其机制的实验研究
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摘要
众多动物研究表明,在急性心肌梗死后的最终梗死面积中,大约50%是由缺血-再灌注损伤所造成的。虽然缺血预处理仍然是目前已知的最为强大的心肌保护措施,但是由于其需要在心肌缺血发生前实施干预,这显然在急性心肌梗死的情况下是不可能的,所以其临床应用受到了极大地限制。缺血后处理成功地解决了缺血预处理所存在的干预时机选择问题,然而由于其与缺血预处理一样仍然需要有创操作,所以其仅可应用于接受PCI治疗的患者或针对急性心肌缺血而实施的某些心脏手术。药物后处理无需有创操作造成短暂缺血,是更为可行的治疗措施。而阿片类药物在心肌缺血开始前或开始后应用获得的心肌保护作用也在多项研究中被证实,尽管其保护效应相对于缺血预处理较弱。
远隔缺血预处理是另外一种内源性心肌保护措施,即心脏以外的器官或组织经历短暂的缺血后,可增强心脏对后继长时间缺血的耐受力。肢体远隔缺血预处理是采用止血带等简单的工具使肢体经历短暂的缺血,从而触发缺血适应性刺激而使心肌获得类似缺血预处理样的保护作用。因为其操作简单、安全、无创且几乎不需要额外的费用,所以容易临床应用,并极具应用价值。在缺血后处理的心肌保护作用被证实之后,人们很快发现,在心肌缺血期间,恢复冠脉再灌注之前使肢体经历短暂缺血触发的肢体远隔缺血后处理亦可获得心肌保护作用,并且这一干预措施的心肌保护效果在部分动物模型和临床研究中均已得到了初步的验证。与缺血预处理和肢体远隔缺血预处理不同,肢体远隔缺血后处理解决了两者在操作时机选择的问题,而且没有缺血后处理需要有创性操作的缺点,因而具有更高的临床应用前景。但现有研究表明,远隔缺血后处理的心肌保护效应也相对缺血预处理较弱,并且受到多个因素的影响。另外,其内在作用机制也未得到充分研究。
联合不同治疗措施以获得更好的心肌保护效果一直重要的研究方向之一,而缺血后处理、阿片类药物后处理和远隔缺血后处理这三种具有临床应用价值的心肌保护措施的触发机制明显不同。有鉴于此,我们设计了这个随机对照的实验研究,旨在观察缺血后处理、芬太尼后处理和肢体远隔缺血后处理的心肌保护效果,并试图证实三者之间是否存在协同性心肌保护作用。另外,我们还进一步研究了阿片受体、氧自由基和PI3K/Akt信号转导通路在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用中的地位,以探讨其相互作用的内在机制。本研究共分三个部分:
第1部分芬太尼后处理、远隔缺血后处理和缺血后处理对在体大鼠心肌缺血-再灌注损伤保护效应的实验研究
第1部分研究的目的是采用在体大鼠心肌缺血-再灌注损伤模型对比观察芬太尼后处理、远隔缺血后处理和缺血后处理的心肌保护作用,并验证三种干预措施在降低心肌梗死面积方面是否存在协同作用。
将73只成年雄性Sprague Dawley大鼠(体重250～350g)麻醉后随机分为九组:空白对照组(S组,n=5);对照组(C组,n=7);芬太尼后处理组(F组,n=9);肢体远隔缺血后处理组(R组,n=9);缺血后处理组(P组,n=8);联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组,n=9);联合应用芬太尼后处理和缺血后处理组(F-P组,n=8);联合应用肢体远隔缺血后处理和缺血后处理组(R-P组,n=9);联合应用芬太尼后处理、肢体远隔缺血后处理和缺血后处理组(F-R-P组,n=9)。所有大鼠开胸后采用丝线将其冠状动脉左前降支(left anterior descending coronary artery,LAD)套扎做成活结。除S组之外,所有大鼠接受局部心肌缺血30 min(阻断LAD)和再灌注180 min(开放LAD)的处理。C组不采用任何干预措施;F组、F-R组、F-P组和F-R-P组在LAD结扎15 min时缓慢静脉注射芬太尼30μg/kg;R组、F-R组、R-P组和F-R-P组在LAD结扎15 min时采用直径1 mm的弹性止血带结扎大鼠双下肢造成肢体缺血10 min,在开放LAD前5 min恢复双下肢血流灌注;P组、F-P组、R-P组和F-R-P组在LAD结扎30 min后,连续实施三个循环的开放LAD 20s/阻断LAD 20s的缺血后处理,随后完全开放LAD实施再灌注。在实验过程中,连续监测心率(heartrate,HR)、平均动脉压(mean arterial pressure,MAP)和Ⅱ导联心电图(ECG),并保持大鼠直肠温度在36.5～37.5℃之间。在再灌注末抽取动脉血标本,采用大鼠专用试剂盒分别测定血浆乳酸脱氢酶(lactate dehydrogenase,LDH)、肌酸激酶MB同工酶(creatine kinase isoenzyme MB,CK-MB)和血清心肌肌钙蛋白I(Cardiac Troponin-I,cTnI)活性。随后采用伊文氏蓝和氯化三苯基四氮唑双重染色检测受损心肌梗死面积(infraction size,IS%)。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值、心肌缺血后15 min内的血流动力学参数、室性心律失常发生情况均无显著差异。但是,在心肌缺血后15 min到开放再灌注前,F组、F-R组、F-P组和F-R-P组的HR、MAP和心率血压乘积(rate-pressure product,RPP)均显著低于其他组。开放LAD再灌注60 min后,各组HR、MAP和RPP无显著差异。除S组之外,其余各组心肌缺血期室性心律失常的发生情况无显著差异,但是再灌注初期各组室性心律失常的发生情况则存在显著差异。与C组比较,除F组、R组和F-R组之外,其余各组再灌注初期室性心律失常发生显著减少;与F组和R组比较,P组、F-R组、F-P组、R-P组和F-R-P组再灌注初期的室性心律失常评分也显著减低。
各组的LDH活性无显著差异;与C组比较,其余各组的CK-MB和cTnI活性以及IS%值均显著降低。在F组、R组和P组之间,CK-MB和cTnI活性在R组最低而P组最高。在F组、R组和P组之间,R组的IS%值较F组和P组显著降低(R组48.4±1.4%vs.F组55.6±2.2%和P组54.2±4.4%)。析因分析结果显示,芬太尼后处理和远隔缺血后处理在降低IS%值方面具有协同作用;而芬太尼后处理和缺血后处理、远隔缺血后处理和缺血后处理之间无显著的交互作用;联合应用芬太尼后处理、缺血后处理和远隔缺血后处理不能进一步降低IS%值,提示三种措施间也无二级交互作用存在。
第2部分氧自由基和阿片受体在联合应用芬太尼后处理和远隔缺血后处理心肌保护效应中的作用和地位
根据第1部分的研究结果,我们设计了这部分实验,其目的是探讨阿片受体和氧自由基在联合应用芬太尼后处理和肢体远隔缺血后处理心肌保护作用中的地位。
该部分研究共分三节,每一节中分别应用氧自由基清除剂巯丙酰甘氨酸(N-(2-Mercaptopropionyl)glycine,MPG)、δ受体拮抗剂NTD(Naltrindole hydrochloride)和κ受体拮抗剂nor-BNI(nor-binaltorphimine)探讨了氧自由基、δ受体和κ受体在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用机制中的地位。在每一节中,分别将24只成年雄性Sprague Dawley大鼠(体重250～350g)麻醉后随机分为四组:对照组(C组)、芬太尼后处理组(F组)、肢体远隔缺血后处理组(R组)以及联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组)。各组大鼠除接受与第1部分对应组相同的心肌缺血-再灌注过程和干预措施之外,并在心肌缺血开始前分别静脉应用MPG、NTD和nor-BNI。
结果显示,与第一部分的对应组比较,MPG、NTD和nor-BNI对大鼠的血流动力学参数和IS%值无显著影响。在应用MPG后,F组和R组的CK-MB和cTnI活性均显著低于C组;但F组和R组的CK-MB和cTnI活性无显著差异;F-R组的CK-MB活性较F组显著降低;但F组、R组和F-R组的cTnI活性无显著差异。与C组相比,R组的IS%无显著差异,但F组和F-R组的IS%显著降低;且F组和F-R组的IS%无显著差异。
应用nor-BNI后,与C组比较,F组、R组和F-R组的CK-MB和cTnI活性均显著降低;虽然F组和R组的CK-MB和cTnI活性无显著差异,但F组却显著高于F-R组。与C组相比,F组的IS%无显著差异,但R组和F-R组的IS%显著降低;但F组和F-R组的IS%无显著差异。
应用NTD后,与C组比较,F组、R组和F-R组的CK-MB和cTnI活性均显著降低;虽然F组和R组的CK-MB和cTnI活性无显著差异,但却显著高于F-R组。与C组相比,F组、R组和F-R组的IS%显著降低,且F-R组的IS%较F组和F-R组显著降低。
第3部分PI3K/Akt信号转导通路在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用机制中的地位
本部分研究的目的是探索PI3K/Akt信号转导通路对联合应用芬太尼后处理和远隔缺血后处理心肌保护效应的调控作用。
将32只成年雄性Sprague Dawley大鼠(体重250～350 g)麻醉后随机分为四组:对照组(C组)、芬太尼后处理组(F组)、肢体远隔缺血后处理组(R组)以及联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组)。按第1部分的方法对各组大鼠实施相应的处理。在开放LAD实施灌注60 min时结束实验,取大鼠左心室缺血区域内的心肌组织标本。随机从每组8个标本中选出5个标本抽提总RNA,将来自同一组的RNA等量混合后与寡核苷酸PI3K/Akt信号传导通路基因芯片杂交,以尽可能减少个体差异。对每个基因点的表达值采用管家基因的平均值进行标准化校正后,以组间的倍数值作为最终结果值。为了验证基因芯片的检测结果,在获得的RAN样品中,每组随机抽取3个,采用实时定量PCR技术对基因芯片检测结果中组间存在差异的2个基因(Cyclin D1和IGF1)进行验证性检测。从余下的心肌标本(每组3个)中提取组织蛋白,采用免疫蛋白印迹分析技术检测心肌标本内磷酸化Akt蛋白的浓度。
基因芯片检测结果显示,许多检测基因的表达情况在四组之间存在显著差异。与C组比较,F组共有12个基因的表达发生显著改变,其中9个基因的表达显著上调和3个基因的表达显著下调。与C组比较,R组有7个基因的表达发生显著改变,其中2个基因的表达显著上调和5个基因的表达显著下调。与C组比较,在F-R组,共有33个基因的表达较C组显著上调,而无基因表达下调。
实时定量PCR检测结果显示,Cyclin D1和IGF1表达水平的组间倍数值与基因芯片检测结果相近。蛋白印记分析结果显示,与C组比较,F组、R组和F-R组心肌标本内磷酸化Akt蛋白表达量增高;而与F组和R组比较,F-R组心肌标本内磷酸化Akt蛋白表达量进一步增高。
结论
通过本研究,我们得出以下结论:
1.芬太尼后处理、远隔缺血后处理和缺血后处理对大鼠心肌缺血-再灌注损伤的保护效果不尽相同。与芬太尼后处理和缺血后处理比较,远隔缺血后处理降低IS%值的效果更明显;与芬太尼后处理比较,缺血后处理可更有效地抑制再灌注初期室性心律失常的发生。但是,远隔缺血后处理无抑制心再灌注初期室性心律失常的作用。
2.在减少IS%值方面,芬太尼后处理和远隔缺血后处理之间存在协同作用;但是缺血后处理和芬太尼后处理、缺血后处理和远隔缺血后处理之间则无交互作用,并且联合应用芬太尼后处理、缺血后处理和远隔缺血后处理三干预措施亦不能进一步增强心肌保护效果。
3.活性氧是远隔缺血后处理心肌保护效应的重要介质,其在联合应用芬太尼后处理和远隔缺血后处理的协同心肌保护效应中亦发挥着重要作用,但是其对芬太尼后处理的心肌保护效应无重要影响。
4.κ受体参与了芬太尼后处理的心肌保护效应,并且在联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护作用中也发挥着重要作用,但是其在肢体远隔缺血后处理的心肌保护效应中无显著作用。δ受体在芬太尼后处理的心肌保护效应中无重要作用,但是其参与了肢体远隔缺血后处理的心肌保护效应,并且在联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护效应中同样发挥着重要作用。
5.联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护效应可能是通过进一步激活PI3K/Akt信号转导通路获得的,并且调控该信号转导通路相关基因表达可能是两者协同作用的重要分子基础。
Background
Many animal studies have shown that after acute myocardial infarction,the ischemia reperfusion(I/R) injury is responsible for up to 50%of the final infarct size.Although the ischemia preconditioning(IPC) remains the most powerful cardioprotective measure,but its clinical application has been hampered by the requirement of intervention before onset of acute myocardial ischemia,which is clearly impossible in the setting of an acute myocardial infarction.Ischemia postconditioning(IPOC) can be triggered during the clinically applicable time period of reperfusion,but it has the same major limitation as the IPC,i.e.the requirement of an invasive protocol which can only be utilized in the patients undergoing percutaneous coronary intervention(PCI) or special surgery for acute myocardial ischemia. Pharmacological postconditioning(PPOC) is a possible alternative method that may substitute invasive treatments of the short ischemic insults.Also,it has been demonstrated that whenever given before or after myocardial ischemia initiation in many studies,opioid can induce cardioprotective effect,though its effect is somewhat weaker compared with the IPC.
Remote preconditioning(RIPC) is another endogenous cardioprotective method,i.e. brief ischemia stimulus on organ or tissue outside of heart would render the heart more tolerant to the subsequential prolonged ischemia.Limb RIPC is triggered by brief limb ischemia,which can be manipulated with the simple tools like tourniquet.Resemble to the IPC,it can produce the cardioprotection by inducing ischemic conditioning stimulus. Because limb RIPC procedure is simple,safe,non-invasive and cost less,it is feasible and has a great value in clinical practice.After the cardioprotection of IPOC against ischemia-reperfusion injury is confirmed,the brief limb ischemia during tong term myocardial ischemia and before coronary artery reperfusion,i.e.the limb remote ischemia postconditioning(RIPOC),has also been immediately shown to produce cardioprotection in some animal models and clinical trials.In contrast to IPC and limb RIPC,limb RIPOC can be triggered after ischemic insult.Also,it doesn't need invasive intervention as IPOC does. Therefore,limb RIPOC may have a promising future in clinical scenario.However,the available data show that cardioprotection induced by RIPOC is weaker compared with IPC, and can be affected by multiple factors.Furthermore,the detailed mechanisms of cardioprotection induced by RIPOC have not been studied extensively.
Combination with different interventions to obtain an augmented cardioprotective effect is always one of the most popular research focuses.Moreover,IPOC,RIPOC and fentanyl PPOC are three cardioprotective measures with significant clinical value and are triggered by different mechanisms.Therefore,we designed this randomized,controlled animal trial.Our purposes were:1) to investigate cardioprotective effects of IPOC,RIPOC and fentanyl PPOC;2) to determine whether a combination of IPOC,RIPOC and fentanyl PPOC could obtain synergistic cardioprotective effect,and 3) to assess the roles of ROS, opioid receptors and PI3K/Akt signal pathway in the cardioprotection of combined fentanyl PPOC and RIPOC,in order to explore the inherent mechanism of the interaction in the cardioprotection between fentanyl PPOC and RIPOC.This trial was divided into the three parts.
Part 1 Experimental study of protective effects of fentanyl postconditioning,remote postconditioning and ischemia postconditioning against rat myocardial ischemia-reperfusion injury in vivo
In this experiment,an in vivo rat model of myocardial I/R injury was used to compare the cardioprotective effects of fentanyl PPOC,RIPOC and IPOC,and to determine whether there was any synergistic effect in myocardial infarct size sparing among the three interventions.
Seventy-three anesthetized male Sprague Dawley rats(weighed 250 to 350 g) were randomly allocated into the nine groups:sham group(group S,n=5),control group(group C, n=7),fentanyl PPOC group(group F,n=9);RIPOC group(group R,n=9),IPOC group (group P,n=8),combined fentanyl PPOC and RIPOC group(group F-R,n=9),combined fentanyl PPOC and IPOC group(group F-P,n=9),combined RIPOC and IPOC group (group R-P,n=9),and combined fentanyl PPOC,RIPOC and IPOC group(group F-R-P, n=9).All rats were opened chest,and the left anterior descending coronary artery(LAD) was encircled with a suture to make a snare.Except for the group S,in the other groups, LAD was ligated for 30 min(ischemia) followed by a 180-min reperfusion(LAD open) in vivo.In group C,no additional intervention was performed.In groups F,F-R,F-P and F-R-P, fentanyl 30μg/kg was slowly injected intravenously at 15 min after LAD ligation.In groups R,F-R,R-P and F-R-P,the bilateral hind limbs underwent a 10-min ischemia which started at 15 min after LAD ligation,and limb blood supply was restored at 5 min before reperfusion.Limb ischemia was produced by placing a thin elastic tourniquet(1-mm diameter) around the upper third of the hind extremity in tight position,closed by a knot to stop the arterial blood supply in the hind limbs.In groups P,F-P,R-P and F-R-P,at 30 min after LAD ligation,IPOC was done with successive three cycles of a 20 s LAD open followed by a 20 s LAD re-occlusion.Throughout the experiment,heart rate(HR),mean arterial pressure(MAP),and a leadⅡelectrocardiogram were continuously monitored. Also,rectal temperature was kept between 36.5℃to 37.5℃.At the end of reperfusion, arterial blood sample was obtained to quantify plasma activity of lactate dehydrogenase (LDH),creatine kinase isoenzyme MB(CK-MB) and serum activity of cardiac troponin I (cTnI) using the kits specifically for rat LDH,CK-MB and cTnI,respectively.Also,the infarct size(IS%) was evaluated using the Evans blue and triphenyltetrazolium chloride (TTC) staining.
The results showed no significant differences among all groups in weight,rectal temperature,baselines of hemodynamic variables before LAD ligation(P＞0.05),and hemodynamic variables and incidences of ventricular arrhythmias in the first 15 min after LAD ligation(P＞0.05).During the period from 15 min after LAD ligation to initiation of reperfusion,HR,MAP and rate-pressure product(RPP) were significantly lower in groups F, F-R,F-P and F-R-P comparing with other groups.There was no significant difference in HR, MAP and RPP at 60 min after reperfusion among all groups.Except for group S,there were no significant differences in the incidences of ventricular arrhythmias during LAD ligation among all groups,but significant differences in the incidences of ventricular arrhythmias during initial period of reperfusion among all groups.As compared with group C, ventricular arrhythmia during initial period of reperfusion significantly decreased in other groups but no groups F,R and F-R.Also,arrhythmic score during initial period of reperfusion was lower in groups P,F-R,F-P,R-P and F-R-P than in groups F.and R.
There was no significant difference in LDH activity among all groups.As compared with group C,the activity levels of CK-MB and cTnI,and IS%decreased significantly in other groups.Among the groups F,R and P,activity levels of CK-MB and cTnI were highest in group P,and lowest in group R.IS%was significantly lower in group R(48.4±1.4%) compared with the groups F and P(55.6±2.2%and 54.2±4.4%,respectively).The restuts of factor analysis showed existence of a synergetic effect in the infract size sparing between fentanyl PPOC and RIPOC.However,there were no significant interactions in the infract size sparing between fentanyl PPOC and IPOC,and between RIPOC with IPOC.As compared with group F-R,in group F-R-P,a combination with fentanyl PPOC,RIPOC and IPOC could not further reduce infarct size,suggesting ho level-2 interaction among the three interventions.
Part 2 Roles of reactive oxygen species and opioid receptors in cardioprotection of combined fentanyl PPOC and RIPOC
Based the results from part-one experiment,we designed part-two experiment to assess the roles of reactive oxygen species(ROS) and opioid receptors in cardioprotective effect of combined fentanyl PPOC and RIPOC.
This part experiment was divided into the three subunits,in which ROS scavenger [N-(2-mercaptopropionyl) glycine,MPG,),selective delta-receptor antagonist(naltrindole, NTD) and selective kappa-receptor antagonist(nor-binaltorphimine,nor-BNI) were used, respectively.Our aims were to explore the roles of ROS,κreceptor andδreceptor in cardioprotective effect of combined fentanyl PPOC and RIPOC.In each subunit,24 anesthetized male Sprague Dawley rats(weighed 250 to 350 g)were randomly allocated into the four groups:control group(group C),fentanyl PPOC group(group F),RIPOC group(group R),and combined fentanyl PPOC and RIPOC group(group F-R).
In the three subunits,all rats were treated with the myocardial I/R in vivo and the fentanyl PPOC or/and limb RIPOC according to the corresponding strategies used in part-one experiment.According to subunit assignments,moreover,MPG,NTD and nor-BNI were also administered intravenously to the rats,respectively,before LAD ligation
The results showed that MPG,NTD and nor-BNI did not significantly change the hemodynamic variables and IS%in group C compared with group C in part-one experiment. When MPG was administered,activity levels of CK-MB and cTnI were significantly lower in groups F and R than in group C,but did not significantly differ between groups F and R. The activity level of CK-MB was significantly lower in group F-R compared with group F. However,there was no significant difference in activity level of cTnI among groups F,R and F-R.As compared with group C,IS%in group R did not significantly change,but IS% in groups F and F-R decreased significantly.The IS%was not different between groups F and F-R.
When nor-BNI was administered,activity levels of CK-MB and cTnI were significantly lower in groups F,R and F-R than in group C.The activity levels of CK-MB and cTnI in groups F and R were not different,but they were higher than those in group F-R. As compared with group C,IS%in group F did not significantly change,but IS%in groups R and F-R decreased significantly.The IS%was not different between groups R and F-R.
When NTD was administered,activity levels of CK-MB and cTnI were significantly lower in groups F,R and F-R compared with group C.The activity levels of CK-MB and cTnI in groups F and R were not different,but they were higher than those in group F-R.As compared with group C,IS%in groups F,R and F-R decreased significantly.The IS%in groups F and R did not differ,but the IS%in group F-R was significantly lower than those in groups F and R.
Part 3 Role of the PI3K/Akt signal pathway in cardioprotective effect of combined fentanyl PPOC and RIPOC
The aim of part 3 experiment was to explore the modulating role of PI3K/Akt signal pathway in cardioprotective effect of combined fentanyl PPOC and RIPOC.
Thirty-two anesthetized male Sprague Dawley rats(weighed 250 to 350 g) rats were randomly allocated into the four groups:control group(group C),fentanyl PPOC group (group F),RIPOC group(group R),and combined fentanyl PPOC and RIPOC group(group F-R).All rats were treated with the myocardial I/R in vivo and the fentanyl PPOC or/and RIPOC according to the corresponding strategies used in part one.At the 60 min after reperfusion by LAD open,hearts of the rats were harvested,and the myocardial samples from the area at risk in the left ventricle were separated.Total RNA were extracted from 5 of the eight subjects.To reduce the individual variability as far as possible,the RNA samples from the same group were equivalently pooled and then hybridized to an oligo GEArray(?) Rat PI3K/Akt signaling pathway microarray.Corrected spot intensities were normalized to averages of the housekeeping genes and the final values were presented as a ratio between the groups.To validate the result of the microarray,the real-time quantitative PCR (qRT-PCR) was used to quantify the expression of two genes(randomly selected from the genes whose expression were significantly different among groups) in three samples randomly selected from acquired RNA samples in each group.For the remaining 3 of the eight myocardial samples,Western-blotting technique was used to analyze the expression of the phosphorylated Akt.
The results showed that expression of many detected genes relating to PI3K/Akt signal pathway was significantly different among the four groups.As compared with group C,in group F,expression of 12 genes changed significantly,in which 9 showed a significant up-regulated expression and 3 present a significant down-regulated expression.As compared with group C,in group R,expression of 7 genes changed significantly,in which 2 showed a significant up-regulated expression and 5 present a significant down-regulated expression.As compared with group C,in group F-R,a total number of 33 genes showed a significant up-regulated expression,and no gene present a down-regulated expression.
The results of the qRT-PCR test showed similar ratios in expression levels of genes cyclin D1 and IGF1 to those of microarray.The Western-blotting analysis revealed that the expression of phosphorylated Akt in myocardium increased significantly in groups F,R and F-R compared with group C.The expression of phosphorylated Akt in myocardium was also stronger in group F-R than in groups F and R.
Conclusions
Based on the results of all experiments,the following conclusions could be drawn:
1.Cardioprotective effects induced by fentanyl PPOC,IPOC and limb RIPOC were not all same.As compared with fentanyl PPOC and IPOC,limb RIPOC was more powerful in the infarct-sparing.As compared with fentanyl PPOC,IPOC was more effective in anti-arrhythmia during initial period of reperfusion.However,limb RIPOC didn't show a significant inhibition on arrhythmia during initial period of reperfusion.
2.There was a synergistic interaction in infarct-sparing effect between fentanyl PPOC and RIPOC,but no interaction in infarct-sparing effect between fentanyi PPOC and IPOC, or between IPOC and limb RIPOC.Also,a combination of fentanyl PPOC,IPOC and limb RIPOC could not further enhance cardioprotection.
3.ROS was an important mediator of the cardioprotection by RIPOC,and it played an important role in the synergistic cardioprotection by combined fentanyl PPOC and RIPOC. However,ROS was not involved in the cardioprotection of fentanyl PPOC.
4.Theκreceptor was involved in the cardioprotection of fentanyl PPOC,and it played an important role in the synergistic cardioprotection by combined the fentanyl PPOC and RIPOC.However,it was not involved in the cardioprotection of RIPOC.Theδreceptor was not related to the cardioprotection of fentanyl PPOC,but it was involved in the cardioprotection of RIPOC and was also crucial to synergistic cardioprotection by combined fentanyl PPOC and RIPOC.
5.The synergistic cardioprotection by combined fentanyl PPOC and RIPOC might be contributed to enhanced activation of PI3K/Akt signal pathway.Also,modulating expression genes relating to the PI3K/Akt signal pathway was perhaps the important molecular basis of the synergistic cardioprotection by combined fentanyl PPOC and limb RIPOC.
远隔缺血预处理是另外一种内源性心肌保护措施,即心脏以外的器官或组织经历短暂的缺血后,可增强心脏对后继长时间缺血的耐受力。肢体远隔缺血预处理是采用止血带等简单的工具使肢体经历短暂的缺血,从而触发缺血适应性刺激而使心肌获得类似缺血预处理样的保护作用。因为其操作简单、安全、无创且几乎不需要额外的费用,所以容易临床应用,并极具应用价值。在缺血后处理的心肌保护作用被证实之后,人们很快发现,在心肌缺血期间,恢复冠脉再灌注之前使肢体经历短暂缺血触发的肢体远隔缺血后处理亦可获得心肌保护作用,并且这一干预措施的心肌保护效果在部分动物模型和临床研究中均已得到了初步的验证。与缺血预处理和肢体远隔缺血预处理不同,肢体远隔缺血后处理解决了两者在操作时机选择的问题,而且没有缺血后处理需要有创性操作的缺点,因而具有更高的临床应用前景。但现有研究表明,远隔缺血后处理的心肌保护效应也相对缺血预处理较弱,并且受到多个因素的影响。另外,其内在作用机制也未得到充分研究。
联合不同治疗措施以获得更好的心肌保护效果一直重要的研究方向之一,而缺血后处理、阿片类药物后处理和远隔缺血后处理这三种具有临床应用价值的心肌保护措施的触发机制明显不同。有鉴于此,我们设计了这个随机对照的实验研究,旨在观察缺血后处理、芬太尼后处理和肢体远隔缺血后处理的心肌保护效果,并试图证实三者之间是否存在协同性心肌保护作用。另外,我们还进一步研究了阿片受体、氧自由基和PI3K/Akt信号转导通路在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用中的地位,以探讨其相互作用的内在机制。本研究共分三个部分:
第1部分芬太尼后处理、远隔缺血后处理和缺血后处理对在体大鼠心肌缺血-再灌注损伤保护效应的实验研究
第1部分研究的目的是采用在体大鼠心肌缺血-再灌注损伤模型对比观察芬太尼后处理、远隔缺血后处理和缺血后处理的心肌保护作用,并验证三种干预措施在降低心肌梗死面积方面是否存在协同作用。
将73只成年雄性Sprague Dawley大鼠(体重250～350g)麻醉后随机分为九组:空白对照组(S组,n=5);对照组(C组,n=7);芬太尼后处理组(F组,n=9);肢体远隔缺血后处理组(R组,n=9);缺血后处理组(P组,n=8);联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组,n=9);联合应用芬太尼后处理和缺血后处理组(F-P组,n=8);联合应用肢体远隔缺血后处理和缺血后处理组(R-P组,n=9);联合应用芬太尼后处理、肢体远隔缺血后处理和缺血后处理组(F-R-P组,n=9)。所有大鼠开胸后采用丝线将其冠状动脉左前降支(left anterior descending coronary artery,LAD)套扎做成活结。除S组之外,所有大鼠接受局部心肌缺血30 min(阻断LAD)和再灌注180 min(开放LAD)的处理。C组不采用任何干预措施;F组、F-R组、F-P组和F-R-P组在LAD结扎15 min时缓慢静脉注射芬太尼30μg/kg;R组、F-R组、R-P组和F-R-P组在LAD结扎15 min时采用直径1 mm的弹性止血带结扎大鼠双下肢造成肢体缺血10 min,在开放LAD前5 min恢复双下肢血流灌注;P组、F-P组、R-P组和F-R-P组在LAD结扎30 min后,连续实施三个循环的开放LAD 20s/阻断LAD 20s的缺血后处理,随后完全开放LAD实施再灌注。在实验过程中,连续监测心率(heartrate,HR)、平均动脉压(mean arterial pressure,MAP)和Ⅱ导联心电图(ECG),并保持大鼠直肠温度在36.5～37.5℃之间。在再灌注末抽取动脉血标本,采用大鼠专用试剂盒分别测定血浆乳酸脱氢酶(lactate dehydrogenase,LDH)、肌酸激酶MB同工酶(creatine kinase isoenzyme MB,CK-MB)和血清心肌肌钙蛋白I(Cardiac Troponin-I,cTnI)活性。随后采用伊文氏蓝和氯化三苯基四氮唑双重染色检测受损心肌梗死面积(infraction size,IS%)。
结果显示,各组大鼠的一般情况、心肌缺血前血流动力学参数的基础值、心肌缺血后15 min内的血流动力学参数、室性心律失常发生情况均无显著差异。但是,在心肌缺血后15 min到开放再灌注前,F组、F-R组、F-P组和F-R-P组的HR、MAP和心率血压乘积(rate-pressure product,RPP)均显著低于其他组。开放LAD再灌注60 min后,各组HR、MAP和RPP无显著差异。除S组之外,其余各组心肌缺血期室性心律失常的发生情况无显著差异,但是再灌注初期各组室性心律失常的发生情况则存在显著差异。与C组比较,除F组、R组和F-R组之外,其余各组再灌注初期室性心律失常发生显著减少;与F组和R组比较,P组、F-R组、F-P组、R-P组和F-R-P组再灌注初期的室性心律失常评分也显著减低。
各组的LDH活性无显著差异;与C组比较,其余各组的CK-MB和cTnI活性以及IS%值均显著降低。在F组、R组和P组之间,CK-MB和cTnI活性在R组最低而P组最高。在F组、R组和P组之间,R组的IS%值较F组和P组显著降低(R组48.4±1.4%vs.F组55.6±2.2%和P组54.2±4.4%)。析因分析结果显示,芬太尼后处理和远隔缺血后处理在降低IS%值方面具有协同作用;而芬太尼后处理和缺血后处理、远隔缺血后处理和缺血后处理之间无显著的交互作用;联合应用芬太尼后处理、缺血后处理和远隔缺血后处理不能进一步降低IS%值,提示三种措施间也无二级交互作用存在。
第2部分氧自由基和阿片受体在联合应用芬太尼后处理和远隔缺血后处理心肌保护效应中的作用和地位
根据第1部分的研究结果,我们设计了这部分实验,其目的是探讨阿片受体和氧自由基在联合应用芬太尼后处理和肢体远隔缺血后处理心肌保护作用中的地位。
该部分研究共分三节,每一节中分别应用氧自由基清除剂巯丙酰甘氨酸(N-(2-Mercaptopropionyl)glycine,MPG)、δ受体拮抗剂NTD(Naltrindole hydrochloride)和κ受体拮抗剂nor-BNI(nor-binaltorphimine)探讨了氧自由基、δ受体和κ受体在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用机制中的地位。在每一节中,分别将24只成年雄性Sprague Dawley大鼠(体重250～350g)麻醉后随机分为四组:对照组(C组)、芬太尼后处理组(F组)、肢体远隔缺血后处理组(R组)以及联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组)。各组大鼠除接受与第1部分对应组相同的心肌缺血-再灌注过程和干预措施之外,并在心肌缺血开始前分别静脉应用MPG、NTD和nor-BNI。
结果显示,与第一部分的对应组比较,MPG、NTD和nor-BNI对大鼠的血流动力学参数和IS%值无显著影响。在应用MPG后,F组和R组的CK-MB和cTnI活性均显著低于C组;但F组和R组的CK-MB和cTnI活性无显著差异;F-R组的CK-MB活性较F组显著降低;但F组、R组和F-R组的cTnI活性无显著差异。与C组相比,R组的IS%无显著差异,但F组和F-R组的IS%显著降低;且F组和F-R组的IS%无显著差异。
应用nor-BNI后,与C组比较,F组、R组和F-R组的CK-MB和cTnI活性均显著降低;虽然F组和R组的CK-MB和cTnI活性无显著差异,但F组却显著高于F-R组。与C组相比,F组的IS%无显著差异,但R组和F-R组的IS%显著降低;但F组和F-R组的IS%无显著差异。
应用NTD后,与C组比较,F组、R组和F-R组的CK-MB和cTnI活性均显著降低;虽然F组和R组的CK-MB和cTnI活性无显著差异,但却显著高于F-R组。与C组相比,F组、R组和F-R组的IS%显著降低,且F-R组的IS%较F组和F-R组显著降低。
第3部分PI3K/Akt信号转导通路在联合应用芬太尼后处理和远隔缺血后处理心肌保护作用机制中的地位
本部分研究的目的是探索PI3K/Akt信号转导通路对联合应用芬太尼后处理和远隔缺血后处理心肌保护效应的调控作用。
将32只成年雄性Sprague Dawley大鼠(体重250～350 g)麻醉后随机分为四组:对照组(C组)、芬太尼后处理组(F组)、肢体远隔缺血后处理组(R组)以及联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组)。按第1部分的方法对各组大鼠实施相应的处理。在开放LAD实施灌注60 min时结束实验,取大鼠左心室缺血区域内的心肌组织标本。随机从每组8个标本中选出5个标本抽提总RNA,将来自同一组的RNA等量混合后与寡核苷酸PI3K/Akt信号传导通路基因芯片杂交,以尽可能减少个体差异。对每个基因点的表达值采用管家基因的平均值进行标准化校正后,以组间的倍数值作为最终结果值。为了验证基因芯片的检测结果,在获得的RAN样品中,每组随机抽取3个,采用实时定量PCR技术对基因芯片检测结果中组间存在差异的2个基因(Cyclin D1和IGF1)进行验证性检测。从余下的心肌标本(每组3个)中提取组织蛋白,采用免疫蛋白印迹分析技术检测心肌标本内磷酸化Akt蛋白的浓度。
基因芯片检测结果显示,许多检测基因的表达情况在四组之间存在显著差异。与C组比较,F组共有12个基因的表达发生显著改变,其中9个基因的表达显著上调和3个基因的表达显著下调。与C组比较,R组有7个基因的表达发生显著改变,其中2个基因的表达显著上调和5个基因的表达显著下调。与C组比较,在F-R组,共有33个基因的表达较C组显著上调,而无基因表达下调。
实时定量PCR检测结果显示,Cyclin D1和IGF1表达水平的组间倍数值与基因芯片检测结果相近。蛋白印记分析结果显示,与C组比较,F组、R组和F-R组心肌标本内磷酸化Akt蛋白表达量增高;而与F组和R组比较,F-R组心肌标本内磷酸化Akt蛋白表达量进一步增高。
结论
通过本研究,我们得出以下结论:
1.芬太尼后处理、远隔缺血后处理和缺血后处理对大鼠心肌缺血-再灌注损伤的保护效果不尽相同。与芬太尼后处理和缺血后处理比较,远隔缺血后处理降低IS%值的效果更明显;与芬太尼后处理比较,缺血后处理可更有效地抑制再灌注初期室性心律失常的发生。但是,远隔缺血后处理无抑制心再灌注初期室性心律失常的作用。
2.在减少IS%值方面,芬太尼后处理和远隔缺血后处理之间存在协同作用;但是缺血后处理和芬太尼后处理、缺血后处理和远隔缺血后处理之间则无交互作用,并且联合应用芬太尼后处理、缺血后处理和远隔缺血后处理三干预措施亦不能进一步增强心肌保护效果。
3.活性氧是远隔缺血后处理心肌保护效应的重要介质,其在联合应用芬太尼后处理和远隔缺血后处理的协同心肌保护效应中亦发挥着重要作用,但是其对芬太尼后处理的心肌保护效应无重要影响。
4.κ受体参与了芬太尼后处理的心肌保护效应,并且在联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护作用中也发挥着重要作用,但是其在肢体远隔缺血后处理的心肌保护效应中无显著作用。δ受体在芬太尼后处理的心肌保护效应中无重要作用,但是其参与了肢体远隔缺血后处理的心肌保护效应,并且在联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护效应中同样发挥着重要作用。
5.联合应用芬太尼后处理和肢体远隔缺血后处理的协同心肌保护效应可能是通过进一步激活PI3K/Akt信号转导通路获得的,并且调控该信号转导通路相关基因表达可能是两者协同作用的重要分子基础。
Background
Many animal studies have shown that after acute myocardial infarction,the ischemia reperfusion(I/R) injury is responsible for up to 50%of the final infarct size.Although the ischemia preconditioning(IPC) remains the most powerful cardioprotective measure,but its clinical application has been hampered by the requirement of intervention before onset of acute myocardial ischemia,which is clearly impossible in the setting of an acute myocardial infarction.Ischemia postconditioning(IPOC) can be triggered during the clinically applicable time period of reperfusion,but it has the same major limitation as the IPC,i.e.the requirement of an invasive protocol which can only be utilized in the patients undergoing percutaneous coronary intervention(PCI) or special surgery for acute myocardial ischemia. Pharmacological postconditioning(PPOC) is a possible alternative method that may substitute invasive treatments of the short ischemic insults.Also,it has been demonstrated that whenever given before or after myocardial ischemia initiation in many studies,opioid can induce cardioprotective effect,though its effect is somewhat weaker compared with the IPC.
Remote preconditioning(RIPC) is another endogenous cardioprotective method,i.e. brief ischemia stimulus on organ or tissue outside of heart would render the heart more tolerant to the subsequential prolonged ischemia.Limb RIPC is triggered by brief limb ischemia,which can be manipulated with the simple tools like tourniquet.Resemble to the IPC,it can produce the cardioprotection by inducing ischemic conditioning stimulus. Because limb RIPC procedure is simple,safe,non-invasive and cost less,it is feasible and has a great value in clinical practice.After the cardioprotection of IPOC against ischemia-reperfusion injury is confirmed,the brief limb ischemia during tong term myocardial ischemia and before coronary artery reperfusion,i.e.the limb remote ischemia postconditioning(RIPOC),has also been immediately shown to produce cardioprotection in some animal models and clinical trials.In contrast to IPC and limb RIPC,limb RIPOC can be triggered after ischemic insult.Also,it doesn't need invasive intervention as IPOC does. Therefore,limb RIPOC may have a promising future in clinical scenario.However,the available data show that cardioprotection induced by RIPOC is weaker compared with IPC, and can be affected by multiple factors.Furthermore,the detailed mechanisms of cardioprotection induced by RIPOC have not been studied extensively.
Combination with different interventions to obtain an augmented cardioprotective effect is always one of the most popular research focuses.Moreover,IPOC,RIPOC and fentanyl PPOC are three cardioprotective measures with significant clinical value and are triggered by different mechanisms.Therefore,we designed this randomized,controlled animal trial.Our purposes were:1) to investigate cardioprotective effects of IPOC,RIPOC and fentanyl PPOC;2) to determine whether a combination of IPOC,RIPOC and fentanyl PPOC could obtain synergistic cardioprotective effect,and 3) to assess the roles of ROS, opioid receptors and PI3K/Akt signal pathway in the cardioprotection of combined fentanyl PPOC and RIPOC,in order to explore the inherent mechanism of the interaction in the cardioprotection between fentanyl PPOC and RIPOC.This trial was divided into the three parts.
Part 1 Experimental study of protective effects of fentanyl postconditioning,remote postconditioning and ischemia postconditioning against rat myocardial ischemia-reperfusion injury in vivo
In this experiment,an in vivo rat model of myocardial I/R injury was used to compare the cardioprotective effects of fentanyl PPOC,RIPOC and IPOC,and to determine whether there was any synergistic effect in myocardial infarct size sparing among the three interventions.
Seventy-three anesthetized male Sprague Dawley rats(weighed 250 to 350 g) were randomly allocated into the nine groups:sham group(group S,n=5),control group(group C, n=7),fentanyl PPOC group(group F,n=9);RIPOC group(group R,n=9),IPOC group (group P,n=8),combined fentanyl PPOC and RIPOC group(group F-R,n=9),combined fentanyl PPOC and IPOC group(group F-P,n=9),combined RIPOC and IPOC group (group R-P,n=9),and combined fentanyl PPOC,RIPOC and IPOC group(group F-R-P, n=9).All rats were opened chest,and the left anterior descending coronary artery(LAD) was encircled with a suture to make a snare.Except for the group S,in the other groups, LAD was ligated for 30 min(ischemia) followed by a 180-min reperfusion(LAD open) in vivo.In group C,no additional intervention was performed.In groups F,F-R,F-P and F-R-P, fentanyl 30μg/kg was slowly injected intravenously at 15 min after LAD ligation.In groups R,F-R,R-P and F-R-P,the bilateral hind limbs underwent a 10-min ischemia which started at 15 min after LAD ligation,and limb blood supply was restored at 5 min before reperfusion.Limb ischemia was produced by placing a thin elastic tourniquet(1-mm diameter) around the upper third of the hind extremity in tight position,closed by a knot to stop the arterial blood supply in the hind limbs.In groups P,F-P,R-P and F-R-P,at 30 min after LAD ligation,IPOC was done with successive three cycles of a 20 s LAD open followed by a 20 s LAD re-occlusion.Throughout the experiment,heart rate(HR),mean arterial pressure(MAP),and a leadⅡelectrocardiogram were continuously monitored. Also,rectal temperature was kept between 36.5℃to 37.5℃.At the end of reperfusion, arterial blood sample was obtained to quantify plasma activity of lactate dehydrogenase (LDH),creatine kinase isoenzyme MB(CK-MB) and serum activity of cardiac troponin I (cTnI) using the kits specifically for rat LDH,CK-MB and cTnI,respectively.Also,the infarct size(IS%) was evaluated using the Evans blue and triphenyltetrazolium chloride (TTC) staining.
The results showed no significant differences among all groups in weight,rectal temperature,baselines of hemodynamic variables before LAD ligation(P＞0.05),and hemodynamic variables and incidences of ventricular arrhythmias in the first 15 min after LAD ligation(P＞0.05).During the period from 15 min after LAD ligation to initiation of reperfusion,HR,MAP and rate-pressure product(RPP) were significantly lower in groups F, F-R,F-P and F-R-P comparing with other groups.There was no significant difference in HR, MAP and RPP at 60 min after reperfusion among all groups.Except for group S,there were no significant differences in the incidences of ventricular arrhythmias during LAD ligation among all groups,but significant differences in the incidences of ventricular arrhythmias during initial period of reperfusion among all groups.As compared with group C, ventricular arrhythmia during initial period of reperfusion significantly decreased in other groups but no groups F,R and F-R.Also,arrhythmic score during initial period of reperfusion was lower in groups P,F-R,F-P,R-P and F-R-P than in groups F.and R.
There was no significant difference in LDH activity among all groups.As compared with group C,the activity levels of CK-MB and cTnI,and IS%decreased significantly in other groups.Among the groups F,R and P,activity levels of CK-MB and cTnI were highest in group P,and lowest in group R.IS%was significantly lower in group R(48.4±1.4%) compared with the groups F and P(55.6±2.2%and 54.2±4.4%,respectively).The restuts of factor analysis showed existence of a synergetic effect in the infract size sparing between fentanyl PPOC and RIPOC.However,there were no significant interactions in the infract size sparing between fentanyl PPOC and IPOC,and between RIPOC with IPOC.As compared with group F-R,in group F-R-P,a combination with fentanyl PPOC,RIPOC and IPOC could not further reduce infarct size,suggesting ho level-2 interaction among the three interventions.
Part 2 Roles of reactive oxygen species and opioid receptors in cardioprotection of combined fentanyl PPOC and RIPOC
Based the results from part-one experiment,we designed part-two experiment to assess the roles of reactive oxygen species(ROS) and opioid receptors in cardioprotective effect of combined fentanyl PPOC and RIPOC.
This part experiment was divided into the three subunits,in which ROS scavenger [N-(2-mercaptopropionyl) glycine,MPG,),selective delta-receptor antagonist(naltrindole, NTD) and selective kappa-receptor antagonist(nor-binaltorphimine,nor-BNI) were used, respectively.Our aims were to explore the roles of ROS,κreceptor andδreceptor in cardioprotective effect of combined fentanyl PPOC and RIPOC.In each subunit,24 anesthetized male Sprague Dawley rats(weighed 250 to 350 g)were randomly allocated into the four groups:control group(group C),fentanyl PPOC group(group F),RIPOC group(group R),and combined fentanyl PPOC and RIPOC group(group F-R).
In the three subunits,all rats were treated with the myocardial I/R in vivo and the fentanyl PPOC or/and limb RIPOC according to the corresponding strategies used in part-one experiment.According to subunit assignments,moreover,MPG,NTD and nor-BNI were also administered intravenously to the rats,respectively,before LAD ligation
The results showed that MPG,NTD and nor-BNI did not significantly change the hemodynamic variables and IS%in group C compared with group C in part-one experiment. When MPG was administered,activity levels of CK-MB and cTnI were significantly lower in groups F and R than in group C,but did not significantly differ between groups F and R. The activity level of CK-MB was significantly lower in group F-R compared with group F. However,there was no significant difference in activity level of cTnI among groups F,R and F-R.As compared with group C,IS%in group R did not significantly change,but IS% in groups F and F-R decreased significantly.The IS%was not different between groups F and F-R.
When nor-BNI was administered,activity levels of CK-MB and cTnI were significantly lower in groups F,R and F-R than in group C.The activity levels of CK-MB and cTnI in groups F and R were not different,but they were higher than those in group F-R. As compared with group C,IS%in group F did not significantly change,but IS%in groups R and F-R decreased significantly.The IS%was not different between groups R and F-R.
When NTD was administered,activity levels of CK-MB and cTnI were significantly lower in groups F,R and F-R compared with group C.The activity levels of CK-MB and cTnI in groups F and R were not different,but they were higher than those in group F-R.As compared with group C,IS%in groups F,R and F-R decreased significantly.The IS%in groups F and R did not differ,but the IS%in group F-R was significantly lower than those in groups F and R.
Part 3 Role of the PI3K/Akt signal pathway in cardioprotective effect of combined fentanyl PPOC and RIPOC
The aim of part 3 experiment was to explore the modulating role of PI3K/Akt signal pathway in cardioprotective effect of combined fentanyl PPOC and RIPOC.
Thirty-two anesthetized male Sprague Dawley rats(weighed 250 to 350 g) rats were randomly allocated into the four groups:control group(group C),fentanyl PPOC group (group F),RIPOC group(group R),and combined fentanyl PPOC and RIPOC group(group F-R).All rats were treated with the myocardial I/R in vivo and the fentanyl PPOC or/and RIPOC according to the corresponding strategies used in part one.At the 60 min after reperfusion by LAD open,hearts of the rats were harvested,and the myocardial samples from the area at risk in the left ventricle were separated.Total RNA were extracted from 5 of the eight subjects.To reduce the individual variability as far as possible,the RNA samples from the same group were equivalently pooled and then hybridized to an oligo GEArray(?) Rat PI3K/Akt signaling pathway microarray.Corrected spot intensities were normalized to averages of the housekeeping genes and the final values were presented as a ratio between the groups.To validate the result of the microarray,the real-time quantitative PCR (qRT-PCR) was used to quantify the expression of two genes(randomly selected from the genes whose expression were significantly different among groups) in three samples randomly selected from acquired RNA samples in each group.For the remaining 3 of the eight myocardial samples,Western-blotting technique was used to analyze the expression of the phosphorylated Akt.
The results showed that expression of many detected genes relating to PI3K/Akt signal pathway was significantly different among the four groups.As compared with group C,in group F,expression of 12 genes changed significantly,in which 9 showed a significant up-regulated expression and 3 present a significant down-regulated expression.As compared with group C,in group R,expression of 7 genes changed significantly,in which 2 showed a significant up-regulated expression and 5 present a significant down-regulated expression.As compared with group C,in group F-R,a total number of 33 genes showed a significant up-regulated expression,and no gene present a down-regulated expression.
The results of the qRT-PCR test showed similar ratios in expression levels of genes cyclin D1 and IGF1 to those of microarray.The Western-blotting analysis revealed that the expression of phosphorylated Akt in myocardium increased significantly in groups F,R and F-R compared with group C.The expression of phosphorylated Akt in myocardium was also stronger in group F-R than in groups F and R.
Conclusions
Based on the results of all experiments,the following conclusions could be drawn:
1.Cardioprotective effects induced by fentanyl PPOC,IPOC and limb RIPOC were not all same.As compared with fentanyl PPOC and IPOC,limb RIPOC was more powerful in the infarct-sparing.As compared with fentanyl PPOC,IPOC was more effective in anti-arrhythmia during initial period of reperfusion.However,limb RIPOC didn't show a significant inhibition on arrhythmia during initial period of reperfusion.
2.There was a synergistic interaction in infarct-sparing effect between fentanyl PPOC and RIPOC,but no interaction in infarct-sparing effect between fentanyi PPOC and IPOC, or between IPOC and limb RIPOC.Also,a combination of fentanyl PPOC,IPOC and limb RIPOC could not further enhance cardioprotection.
3.ROS was an important mediator of the cardioprotection by RIPOC,and it played an important role in the synergistic cardioprotection by combined fentanyl PPOC and RIPOC. However,ROS was not involved in the cardioprotection of fentanyl PPOC.
4.Theκreceptor was involved in the cardioprotection of fentanyl PPOC,and it played an important role in the synergistic cardioprotection by combined the fentanyl PPOC and RIPOC.However,it was not involved in the cardioprotection of RIPOC.Theδreceptor was not related to the cardioprotection of fentanyl PPOC,but it was involved in the cardioprotection of RIPOC and was also crucial to synergistic cardioprotection by combined fentanyl PPOC and RIPOC.
5.The synergistic cardioprotection by combined fentanyl PPOC and RIPOC might be contributed to enhanced activation of PI3K/Akt signal pathway.Also,modulating expression genes relating to the PI3K/Akt signal pathway was perhaps the important molecular basis of the synergistic cardioprotection by combined fentanyl PPOC and limb RIPOC.
引文
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