Apelin对缺血—再灌注损伤导致的心脏功能障碍的保护作用及机制研究
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摘要
背景与目的
本实验室于2008年发现Apelin能够增强心肌细胞SERCA功能并且增加钙瞬变幅度。本研究在以上研究基础上进一步研究Apelin对心肌缺血再灌注的保护作用。不同于已有的大量关于缺血再灌注的保护作用的研究，本研究着重从心肌的功能保护方面进行研究。因为我们相信缺血再灌注损伤除了直接导致心肌细胞凋亡、自噬或者坏死以外，还会导致一部分细胞功能障碍。这部分细胞并没有立即死亡，仍在发挥作用，但细胞的许多生化功能和收缩功能都受到了影响。这种功能方面的研究并不多，但我们认为细胞这时的功能极为重要，一方面良好的细胞功能可以保证即刻的心脏收缩功能，减少心律失常的发生，在临床上也就能减少患者即刻的死亡率。另一方面良好的细胞功能可以保证细胞的正常生理生化功能，并帮助细胞修复损伤，最终减少细胞的死亡。
因此本研究从心肌收缩功能，SR功能，氧化应激状态，蛋白氧化修饰，细胞钙瞬变功能以及心肌代谢状况等几个方面分两部分作了研究。
方法
1.使用大鼠心脏，将心脏主动脉与心脏灌流装置（Langendorff）相连接，进行逆向灌流。同时记录冠脉血流量,左室收缩压(LVSP)以及左心室形成压(LVDP)，同时在整个灌流过程中使用Acknowledge software (Biopac System Inc, USA)不断计算左室内压力的变化率最大值(±dp/dtmax)。采用Global缺血30min再灌注30min的I/R模型。
2.心肌梗死面积采用TTC染色法测定。
3.使用多种方法测量心脏氧化应激状态。测量心脏组织中丙二醛(MDA，一种脂质过氧化产物)的含量。心脏谷胱甘肽（GSH）含量的检测。GSH是谷胱甘肽过氧化酶清除ROS所必需的。测定细胞内氧化还原态的变化(i.e.NADH/NAD+)。
4.心肌肌浆网SR囊泡分离。心脏左室组织被粉碎并混匀两次,每次20s。匀浆缓冲剂(mmol/L)包含10NaHCO3,5NaN3,15Tris-HCl (pH6.8)，以及蛋白酶抑制剂(1μmol/L leupeptin,1μmol/L pepstatin以及100μmol/L phenylmethyl-sulfonylfluoride)。将混合物以9500rpm离心20min，取上清进一步离心19000rpm45min。离心后的沉淀物用缓冲液（0.6mol/LKCl和20mmol/LTris-HCl pH6.8)重悬，以19000rpm45min离心，离心后的沉淀物重悬于0.25mol/L sucrose和10mmol/L histidine (pH7.0)的混合液中。以上实验步骤在0°C至4°C的环境中进行操作。
5.肌浆网钙泵（SERCA）摄取钙的测量。
6.肌浆网钙释放通道蛋白（RyR）活性的测量。使用测量(3H)-ryanodine亲和力的方法测量。
7.分离成年大鼠心肌细胞。
8.建立细胞模拟心脏缺血再灌注模型。
9.测量细胞收缩和钙瞬变。使用fluo-3负载荧光染色心肌细胞。
10.测量细胞内ROS的生成。心肌细胞在室温下负载(DCFH-DA,10μmol/L)1小时。一旦进入细胞，DCFH-DA乙酸盐组在酯酶的作用下裂解产生极性，非荧光产物DCFH积聚在细胞内。活性氧产生氧化荧光产物二氯荧光素（DCF）。负载后，细胞在含有1.25mmol/L钙的改良Joklik MEM液中清洗3次，轻轻重悬然后沉淀去除细胞外DCFH-DA。新鲜分离的心肌细胞置于含介质的定制腔室，它被放置在尼康倒落射荧光显微镜上并与国际光子技术光电倍增管和Deltascan双波长激发荧光分光光度计相连接。在单一的杆状细胞内用Felix软件以1point/second记录DCF荧光（激发波长为488nm，发射波长为530nm）并用×200放大倍数观测。
11.免疫沉淀法测量SERCA和RyR的氧化修饰状态。
12.心脏灌流[1-13C]葡萄糖或2.5mM [3-13C]丙酮酸盐。
13. NMR测量13C光谱和H光谱。
结果
1.100nmol/L和1μmol/LApelin-13组LDH释放量明显减少。
2.各组心肌没有发现明显的心梗。
3. Apelin改善了再灌注后的心脏收缩功能，降低了缺血过程中的左室舒张压，减轻了缺血挛缩的发生和发展。
4. Apelin改善了心肌内的氧化还原状态。
5. Apelin增强了SERCA摄取钙的能力改善了RyR释放钙的能力。
6. Apelin减弱了SERCA和RyR的氧化修饰。
7. Apelin减少了单细胞ROS的生成。
8. Apelin改善了单细胞钙瞬变功能和收缩功能。
9.使用PI3K，PKC，PKC，mitoKATPchannel的抑制剂或阻断剂可以抵消或部分抵消Apelin的保护作用。
10. Apelin增加了心脏缺血时的糖酵解。
11.Apelin增加了心脏缺血时的ATP含量。
12. Apelin增加了丙氨酸转氨酶的活性。
13. Apelin延迟了心肌缺血挛缩的发生时间。
结论
Apelin-13能够保护缺血再灌注损伤的心肌收缩功能，其机制可能是：一方面Apelin抑制心肌产生过多的ROS从而减少SR钙处理蛋白的氧化修饰，维持细胞内钙稳态，减轻钙超载的同时又保证收缩功能需要的钙。其作用依赖于PI3K-PKCs(PKC)-mitoKATPchannel通路。另一方面Apelin能够增加缺血时糖酵解的作用，补充ATP的损失，供应心肌所需能量，同时减轻或延迟缺血挛缩的发生。
Apelin is a peptide ligand for a G-protein coupled receptor (APJ receptor). Apelin/APJsystem is widely expressed in brain, heart, stomach, lung and the vascular system. Apelinregulates cardiovascular function, producing vasodilatory and positive inotropic effect.There is an increasing body of evidence to suggest that Apelin protects the heart againstischemia/reperfusion (I/R) induced infarction, but the mechanism is still controversial.
While irreversible injuries inducing cardiomyocytes necrosis or apoptosis occurredduring I/R, myocardial contractile dysfunction resulting from I/R is also a commonclinical problem in patients with some heart diseases and therapies. But the effect ofApelin on cardiac dysfunction induced by I/R was not well investigated. During I/R, cardiac contractile dysfunction is attributed to the impairment of calcium handlingactivities of the cardiomyocyte. Ca2+enters the cardiomyocyte through the L-type Ca2+channels (LTCC) triggering further release of Ca2+via the ryanodine receptor (RyR) fromthe sarcoplasmic reticulum (SR), which lead to a large increase in cytosolic free calciumconcentration, known as the intracellular [Ca2+] transient ([Ca2+]i). The elevatedintracellular calcium concentration, which stimulates contraction of the myofilaments, isremoved mainly to the SR by the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)and out of the myocytes by the Na+/Ca2+exchanger (NCX) to initiate relaxation.Abnormalities in function of Ca2+handling has been suggested to explain contractiledysfunction of the heart following I/R in the heart.
On the other hand, the increase in reactive oxygen species (ROS) within the first fewminutes of reperfusion has been proposed to explain the I/R-induced contractile changes inthe heart. Furthermore, SR Ca2+uptake and release activities have been reported to bedepressed by ROS in I/R hearts. In fact, exposure of the heart to different species of ROShas been shown to cause structural and functional alterations in the heart that are similarto those seen in I/R; these changes have been demonstrated to be due to abnormalities inCa2+handling by SR and sarcolemma.
Therefore it is likely that, during I/R, over release of ROS impaired the SR Ca2+handling activities in the cardiomyocytes, inducing the contractile dysfunction. Apelincould increase SERCA activity and calcium transient in normal cardiomyocytes, but theeffects of Apelin on ROS and SR in I/R heart have not been investigated.
Survival kinases, such as phosphatidylinositol-3-kinase (PI3K)/Akt and PKC may acton downstream mitochondrial targets to open mitochondrial ATP-sensitive potassium(mitoKATP) channels and to affect cellular survival, reducing both necrosis and apoptosis.The mitoKATPchannels may modulate ROS production, which may lead to a re-activationof a pool of PKCs. In particular, in concert with mitoKATPchannels, theintra-mitochondrial protein kinase C (PKC) activation may take part to the so-called“memory-associated protection”. In previous reports, PI3K/Akt pathway was involved inthe cardioprotective effect of Apelin against I/R. We supposed that these survival kinases and downstream targets might play a role in the effect of Apelin on ROS production andSR function in I/R.
The present study was therefore undertaken for three purposes to examine:1)whether Apelin can improve the cardiac dysfunction induced by I/R;2) if Apelin canprevent abnormalities in ROS production and SR function in I/R hearts;3) the probablyunderlying mechanisms.Methods
1. Heart perfusion
The hearts of male Sprague-Dawley rats were rapidly excised, cannulated to theLangendorff’s apparatus and perfused under a constant pressure of80mmHg withKrebs-Henseleit (K-H) medium containing (mmol/L)120NaCl,25NaHCO3,4.7KCl,1.2KH2PO4,1.2MgSO4,1.25CaCl2, and11glucose (37°C, pH7.4). The left ventricularend-diastolic pressure (LVEDP) was adjusted at5mmHg. Such a volume of balloon wasmaintained throughout the experiment. The coronary flow, left ventricular systolicpressure (LVSP) and left ventricular developed pressure (LVDP) were recorded andmaximum derivatives of the ventricular pressure (±dp/dtmax) were calculated continuouslyby the Acknowledge software.
2. Determination of myocardial infarct sizeInfarct size was determined by2,3,5-triphenyltetrazolium chloride (TTC) staining.
3. Determination of oxidative stress, redox state and nitrotyrosine content in isolatedhearts.
4. Isolation of SR vesicles.
5. Measurement of calcium uptake by SERCA.
6.3H-Ryanodine binding assay.
7. Isolation of adult rat ventricular myocytes and treatment with simulated I/R.
8. Measurement of [Ca2+]i transients and cell shortening in the single cardiomyocyte.
9. Measurement of ROS Generation in cardiomyocytes.
10. Immunoprecipitation with anti-SERCA or anti-RyR antibody.
11. Tissue Biochemistry. Perchloric acid extractions were performed on frozen ventricle tissue.
12. NMR Measurements. All NMR data were acquired on a spectrometer equipped withan Aspect3000series computer and a9.4-T, vertical-bore superconducting magnet.Relative metabolite levels within each spectrum were determined by integration of theareas under each resonance peak of interest using an analysis subroutine within the NMRdedicated software.Results
1. Cardioprotection effects of Apelin-13. A significant reduction in the LDH release inthe100nmol/L and1μmol/L groups was observed.
2. Apelin improved cardiac dysfunction of the I/R hearts.
3. Apelin attenuated ischemic and reperfused contracture.
4. Apelin ameliorated myocardial oxidative stress caused by I/R.
5. Apelin-13restored the activities of SERCA and RyR during I/R.
6. Apelin attenuated the tyrosine nitration of SERCA and maintained theS-glutathiolation of SERCA and S-glutathiolation of RyR in I/R rat hearts.
7. Effect of Apelin-13on ROS Generation during I/R in Cardiomyocytes. To examinethe ROS generation during simulated I/R, we examined the fluorescence of DCFH-loadedcells. The ROS level was found to be increased after reperfusion and Apelin-13reducedthis increase.
8. Apelin-13improved the impairment of Ca2+homeostasis and cell shorteninginduced by I/R.
9. Tissue lactate content was similar, whereas alanine content was higher in controlhearts perfused with pyruvate versus glucose controls.
10. Effects of Apelin on Tissue Metabolites. Apelin treatment did not affect tissuelactate levels under any of the experimental conditions, including ischemia. In contrast,Apelin treatment raised tissue alanine content.
11. Exogenous Apelin was effective in preserving ATP levels at ischemia when glucose was available.
12. Apelin treatment delayed the onset of contracture.
Conclusion: Apelin protects SR function and cardiac performance during I/R byattenuating oxidation of SERCA and RyR and preserving ATP content.
本实验室于2008年发现Apelin能够增强心肌细胞SERCA功能并且增加钙瞬变幅度。本研究在以上研究基础上进一步研究Apelin对心肌缺血再灌注的保护作用。不同于已有的大量关于缺血再灌注的保护作用的研究，本研究着重从心肌的功能保护方面进行研究。因为我们相信缺血再灌注损伤除了直接导致心肌细胞凋亡、自噬或者坏死以外，还会导致一部分细胞功能障碍。这部分细胞并没有立即死亡，仍在发挥作用，但细胞的许多生化功能和收缩功能都受到了影响。这种功能方面的研究并不多，但我们认为细胞这时的功能极为重要，一方面良好的细胞功能可以保证即刻的心脏收缩功能，减少心律失常的发生，在临床上也就能减少患者即刻的死亡率。另一方面良好的细胞功能可以保证细胞的正常生理生化功能，并帮助细胞修复损伤，最终减少细胞的死亡。
因此本研究从心肌收缩功能，SR功能，氧化应激状态，蛋白氧化修饰，细胞钙瞬变功能以及心肌代谢状况等几个方面分两部分作了研究。
方法
1.使用大鼠心脏，将心脏主动脉与心脏灌流装置（Langendorff）相连接，进行逆向灌流。同时记录冠脉血流量,左室收缩压(LVSP)以及左心室形成压(LVDP)，同时在整个灌流过程中使用Acknowledge software (Biopac System Inc, USA)不断计算左室内压力的变化率最大值(±dp/dtmax)。采用Global缺血30min再灌注30min的I/R模型。
2.心肌梗死面积采用TTC染色法测定。
3.使用多种方法测量心脏氧化应激状态。测量心脏组织中丙二醛(MDA，一种脂质过氧化产物)的含量。心脏谷胱甘肽（GSH）含量的检测。GSH是谷胱甘肽过氧化酶清除ROS所必需的。测定细胞内氧化还原态的变化(i.e.NADH/NAD+)。
4.心肌肌浆网SR囊泡分离。心脏左室组织被粉碎并混匀两次,每次20s。匀浆缓冲剂(mmol/L)包含10NaHCO3,5NaN3,15Tris-HCl (pH6.8)，以及蛋白酶抑制剂(1μmol/L leupeptin,1μmol/L pepstatin以及100μmol/L phenylmethyl-sulfonylfluoride)。将混合物以9500rpm离心20min，取上清进一步离心19000rpm45min。离心后的沉淀物用缓冲液（0.6mol/LKCl和20mmol/LTris-HCl pH6.8)重悬，以19000rpm45min离心，离心后的沉淀物重悬于0.25mol/L sucrose和10mmol/L histidine (pH7.0)的混合液中。以上实验步骤在0°C至4°C的环境中进行操作。
5.肌浆网钙泵（SERCA）摄取钙的测量。
6.肌浆网钙释放通道蛋白（RyR）活性的测量。使用测量(3H)-ryanodine亲和力的方法测量。
7.分离成年大鼠心肌细胞。
8.建立细胞模拟心脏缺血再灌注模型。
9.测量细胞收缩和钙瞬变。使用fluo-3负载荧光染色心肌细胞。
10.测量细胞内ROS的生成。心肌细胞在室温下负载(DCFH-DA,10μmol/L)1小时。一旦进入细胞，DCFH-DA乙酸盐组在酯酶的作用下裂解产生极性，非荧光产物DCFH积聚在细胞内。活性氧产生氧化荧光产物二氯荧光素（DCF）。负载后，细胞在含有1.25mmol/L钙的改良Joklik MEM液中清洗3次，轻轻重悬然后沉淀去除细胞外DCFH-DA。新鲜分离的心肌细胞置于含介质的定制腔室，它被放置在尼康倒落射荧光显微镜上并与国际光子技术光电倍增管和Deltascan双波长激发荧光分光光度计相连接。在单一的杆状细胞内用Felix软件以1point/second记录DCF荧光（激发波长为488nm，发射波长为530nm）并用×200放大倍数观测。
11.免疫沉淀法测量SERCA和RyR的氧化修饰状态。
12.心脏灌流[1-13C]葡萄糖或2.5mM [3-13C]丙酮酸盐。
13. NMR测量13C光谱和H光谱。
结果
1.100nmol/L和1μmol/LApelin-13组LDH释放量明显减少。
2.各组心肌没有发现明显的心梗。
3. Apelin改善了再灌注后的心脏收缩功能，降低了缺血过程中的左室舒张压，减轻了缺血挛缩的发生和发展。
4. Apelin改善了心肌内的氧化还原状态。
5. Apelin增强了SERCA摄取钙的能力改善了RyR释放钙的能力。
6. Apelin减弱了SERCA和RyR的氧化修饰。
7. Apelin减少了单细胞ROS的生成。
8. Apelin改善了单细胞钙瞬变功能和收缩功能。
9.使用PI3K，PKC，PKC，mitoKATPchannel的抑制剂或阻断剂可以抵消或部分抵消Apelin的保护作用。
10. Apelin增加了心脏缺血时的糖酵解。
11.Apelin增加了心脏缺血时的ATP含量。
12. Apelin增加了丙氨酸转氨酶的活性。
13. Apelin延迟了心肌缺血挛缩的发生时间。
结论
Apelin-13能够保护缺血再灌注损伤的心肌收缩功能，其机制可能是：一方面Apelin抑制心肌产生过多的ROS从而减少SR钙处理蛋白的氧化修饰，维持细胞内钙稳态，减轻钙超载的同时又保证收缩功能需要的钙。其作用依赖于PI3K-PKCs(PKC)-mitoKATPchannel通路。另一方面Apelin能够增加缺血时糖酵解的作用，补充ATP的损失，供应心肌所需能量，同时减轻或延迟缺血挛缩的发生。
Apelin is a peptide ligand for a G-protein coupled receptor (APJ receptor). Apelin/APJsystem is widely expressed in brain, heart, stomach, lung and the vascular system. Apelinregulates cardiovascular function, producing vasodilatory and positive inotropic effect.There is an increasing body of evidence to suggest that Apelin protects the heart againstischemia/reperfusion (I/R) induced infarction, but the mechanism is still controversial.
While irreversible injuries inducing cardiomyocytes necrosis or apoptosis occurredduring I/R, myocardial contractile dysfunction resulting from I/R is also a commonclinical problem in patients with some heart diseases and therapies. But the effect ofApelin on cardiac dysfunction induced by I/R was not well investigated. During I/R, cardiac contractile dysfunction is attributed to the impairment of calcium handlingactivities of the cardiomyocyte. Ca2+enters the cardiomyocyte through the L-type Ca2+channels (LTCC) triggering further release of Ca2+via the ryanodine receptor (RyR) fromthe sarcoplasmic reticulum (SR), which lead to a large increase in cytosolic free calciumconcentration, known as the intracellular [Ca2+] transient ([Ca2+]i). The elevatedintracellular calcium concentration, which stimulates contraction of the myofilaments, isremoved mainly to the SR by the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)and out of the myocytes by the Na+/Ca2+exchanger (NCX) to initiate relaxation.Abnormalities in function of Ca2+handling has been suggested to explain contractiledysfunction of the heart following I/R in the heart.
On the other hand, the increase in reactive oxygen species (ROS) within the first fewminutes of reperfusion has been proposed to explain the I/R-induced contractile changes inthe heart. Furthermore, SR Ca2+uptake and release activities have been reported to bedepressed by ROS in I/R hearts. In fact, exposure of the heart to different species of ROShas been shown to cause structural and functional alterations in the heart that are similarto those seen in I/R; these changes have been demonstrated to be due to abnormalities inCa2+handling by SR and sarcolemma.
Therefore it is likely that, during I/R, over release of ROS impaired the SR Ca2+handling activities in the cardiomyocytes, inducing the contractile dysfunction. Apelincould increase SERCA activity and calcium transient in normal cardiomyocytes, but theeffects of Apelin on ROS and SR in I/R heart have not been investigated.
Survival kinases, such as phosphatidylinositol-3-kinase (PI3K)/Akt and PKC may acton downstream mitochondrial targets to open mitochondrial ATP-sensitive potassium(mitoKATP) channels and to affect cellular survival, reducing both necrosis and apoptosis.The mitoKATPchannels may modulate ROS production, which may lead to a re-activationof a pool of PKCs. In particular, in concert with mitoKATPchannels, theintra-mitochondrial protein kinase C (PKC) activation may take part to the so-called“memory-associated protection”. In previous reports, PI3K/Akt pathway was involved inthe cardioprotective effect of Apelin against I/R. We supposed that these survival kinases and downstream targets might play a role in the effect of Apelin on ROS production andSR function in I/R.
The present study was therefore undertaken for three purposes to examine:1)whether Apelin can improve the cardiac dysfunction induced by I/R;2) if Apelin canprevent abnormalities in ROS production and SR function in I/R hearts;3) the probablyunderlying mechanisms.Methods
1. Heart perfusion
The hearts of male Sprague-Dawley rats were rapidly excised, cannulated to theLangendorff’s apparatus and perfused under a constant pressure of80mmHg withKrebs-Henseleit (K-H) medium containing (mmol/L)120NaCl,25NaHCO3,4.7KCl,1.2KH2PO4,1.2MgSO4,1.25CaCl2, and11glucose (37°C, pH7.4). The left ventricularend-diastolic pressure (LVEDP) was adjusted at5mmHg. Such a volume of balloon wasmaintained throughout the experiment. The coronary flow, left ventricular systolicpressure (LVSP) and left ventricular developed pressure (LVDP) were recorded andmaximum derivatives of the ventricular pressure (±dp/dtmax) were calculated continuouslyby the Acknowledge software.
2. Determination of myocardial infarct sizeInfarct size was determined by2,3,5-triphenyltetrazolium chloride (TTC) staining.
3. Determination of oxidative stress, redox state and nitrotyrosine content in isolatedhearts.
4. Isolation of SR vesicles.
5. Measurement of calcium uptake by SERCA.
6.3H-Ryanodine binding assay.
7. Isolation of adult rat ventricular myocytes and treatment with simulated I/R.
8. Measurement of [Ca2+]i transients and cell shortening in the single cardiomyocyte.
9. Measurement of ROS Generation in cardiomyocytes.
10. Immunoprecipitation with anti-SERCA or anti-RyR antibody.
11. Tissue Biochemistry. Perchloric acid extractions were performed on frozen ventricle tissue.
12. NMR Measurements. All NMR data were acquired on a spectrometer equipped withan Aspect3000series computer and a9.4-T, vertical-bore superconducting magnet.Relative metabolite levels within each spectrum were determined by integration of theareas under each resonance peak of interest using an analysis subroutine within the NMRdedicated software.Results
1. Cardioprotection effects of Apelin-13. A significant reduction in the LDH release inthe100nmol/L and1μmol/L groups was observed.
2. Apelin improved cardiac dysfunction of the I/R hearts.
3. Apelin attenuated ischemic and reperfused contracture.
4. Apelin ameliorated myocardial oxidative stress caused by I/R.
5. Apelin-13restored the activities of SERCA and RyR during I/R.
6. Apelin attenuated the tyrosine nitration of SERCA and maintained theS-glutathiolation of SERCA and S-glutathiolation of RyR in I/R rat hearts.
7. Effect of Apelin-13on ROS Generation during I/R in Cardiomyocytes. To examinethe ROS generation during simulated I/R, we examined the fluorescence of DCFH-loadedcells. The ROS level was found to be increased after reperfusion and Apelin-13reducedthis increase.
8. Apelin-13improved the impairment of Ca2+homeostasis and cell shorteninginduced by I/R.
9. Tissue lactate content was similar, whereas alanine content was higher in controlhearts perfused with pyruvate versus glucose controls.
10. Effects of Apelin on Tissue Metabolites. Apelin treatment did not affect tissuelactate levels under any of the experimental conditions, including ischemia. In contrast,Apelin treatment raised tissue alanine content.
11. Exogenous Apelin was effective in preserving ATP levels at ischemia when glucose was available.
12. Apelin treatment delayed the onset of contracture.
Conclusion: Apelin protects SR function and cardiac performance during I/R byattenuating oxidation of SERCA and RyR and preserving ATP content.
引文
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