摘要
急性心肌梗死(acute myocardial infarction, AMI)后心室重构(ventricular remodeling, VR)包括梗死区扩展、心室扩张和非梗死区代偿性肥厚,是引起AMI后心衰的病理基础,与缺血后心肌细胞凋亡、肥大、延长、侧向滑移及心肌间质纤维化等密切相关。心肌缺血触发的内质网应激(endoplasmic reticulum stress, ERS)是引起细胞凋亡的主要信号通路。ERS信号通路能诱导C/EBP同源蛋白(C/EBP homologous protein, CHOP)与其他转录因子结合,诱导促凋亡基因表达。我们前期研究证实,CHOP介导的ERS相关凋亡途径,参与大鼠心肌缺血/再灌注损伤及心肌细胞缺氧/复氧损伤。CHOP介导的ERS相关凋亡,是否参与AMI后心室重构的病理过程?尚缺少研究报道。
我们前期研究发现,西洋参茎叶总皂苷(Panax quinquefolium saponin, PQS)可通过抑制炎症反应、降低神经内分泌因子的激活、调节细胞外基质代谢等改善AMI后VR; PQS可改善大鼠心肌缺血再灌注损伤,减轻离体大鼠心肌细胞缺氧/复氧损伤,其机制和抑制过度ERS有关。PQS改善AMI后VR的作用,是否与抑制CHOP介导的ERS相关凋亡有关?以往亦缺少研究。
因此,本研究采用结扎大鼠左冠状动脉前降支建立AMI模型,进一步证实PQS改善AMI后VR的作用,并从CHOP介导的ERS相关凋亡方面,探讨PQS改善AMI后VR的分子机制；采用内质网应激诱导剂毒胡萝卜素(thapsigargin,TG)诱导离体乳大鼠心肌细胞ERS相关凋亡,观察PQS对TG诱导心肌细胞凋亡的影响；以蛋白激酶R样内质网激酶(protein kinase R-like ER kinase, PERK)重组腺病毒感染和RNA干扰(RNA interference, RNAi)方法分别过表达或敲低心肌细胞内质网(endoplasmic reticulum, ER)跨膜蛋白PERK基因,探讨PQS抑制ERS相关凋亡的信号途径。
研究一西洋参茎叶总皂苷改善急性心肌梗死后心室重构的作用
目的：证实西洋参茎叶总皂苷对AMI后心室重构的改善作用
方法：通过结扎大鼠左冠状动脉前降支复制急性心肌梗死模型，术后24h,存活的大鼠随机分为PQS50mg/kg/d组、PQS100mg/kg/d组、PQS200mg/kg/d组、牛磺酸300mg/kg/d组及AMI组(等量饮用水灌胃),每组10只。另设sham组(等量饮用水灌胃)15只。4周后,超声心动图检测左室结构及功能变化、颈动脉插管检测血流动力学、BIOSITE Triage诊断仪测定血浆BNP含量、Evans blue和TTC染色法测定心肌梗死范围、比色法测定非梗死区心肌组织羟脯氨酸含量。
结果：与AMI组比较,低、中、高剂量PQS均可明显降低收缩期及舒张期左室内径、左室舒张末压、血浆BNP水平、心肌梗死范围和心肌组织羟脯氨酸含量(P<0.05),升高射血分数、左室短轴缩短率、平均颈动脉压、左室收缩末压和--dp/dtmax及-dp/dtmax绝对值(P<0.05),且呈剂量依赖性。
结论：PQS减轻AMI后大鼠心脏结构变化、功能损伤和纤维化程度,减轻AMI后心室重构。
研究二西洋参茎叶总皂苷抑制AMI后内质网应激相关凋亡的作用
目的：证实西洋参茎叶总皂苷抑制AMI后ERS相关凋亡的作用。
方法：AMI造模后24h,存活大鼠分组(每组10只)：AMI组(等量饮用水灌胃),PQS200mg/kg/d组、牛磺酸组(300mg/kg/d),另设sham组15只。4周后,TUNEL法检测非梗死区心肌细胞凋亡率,Western blotting检测ERS分子葡萄糖调节蛋白78(GRP78)、钙网蛋白(CRT)、CHOP及凋亡相关蛋白Bcl-2、Bax的表达。
结果：与AMI组比较,PQS200mg/kg/d组非梗死区心肌细胞凋亡率、内质网应激分子GRP78和CRT蛋白表达、ERS凋亡相关分子CHOP和促凋亡蛋白Bax表达均明显降低(P<0.05),抗凋亡蛋白Bcl-2明显升高(P<0.05)。Spearman相关分析发现,CHOP蛋白表达与心肌细胞凋亡率呈显著正相关(r=0.797,P<0.01)。
结论：PQS通过抑制CHOP介导的ERS相关凋亡而减轻AMI后非梗死区心肌细胞凋亡。
研究三西洋参茎叶总皂苷减轻毒胡萝卜素诱导心肌细胞凋亡的作用
目的：证实PQS减轻ERS诱导剂TG诱导心肌细胞凋亡的作用。
方法：原代培养的心肌细胞分为：①Control组：细胞置CO2孵箱37℃,常规培养24h。②TG组：培养液中加1μMTG,作用24h；③、④、⑤、⑥组：分别采用40μg/ml、80μg/ml及160μg/ml PQS及牛磺酸40mM预处理细胞24h后,再向培养液中加入1μM TG作用24h。CCK-8法和流式细胞术检测细胞活性及凋亡率,Western blotting方法检测ERS标志分子GRP78、PERK、CHOP及凋亡相关蛋白Bcl-2、Bax的表达。
结果：与TG组比较,PQS160μg/ml可显著降低细胞凋亡率,升高细胞比活力(P<0.05)；三种不同浓度的PQS均可降低GRP78、PERK、CHOP及Bax蛋白表达,升高Bcl-2蛋白表达(P<0.05),且呈剂量依赖性。
结论：PQS160μg/ml减轻内质网应激诱导剂毒胡萝卜素诱导的心肌细胞凋亡其机理可能与抑制过度ERS相关凋亡有关。
研究四西洋参茎叶总皂苷抑制PERK介导的内质网应激相关凋亡途径的作用
目的：证实PQS通过抑制PERK-eIF2a-ATF4-CHOP减轻心肌细胞凋亡。
方法：原代培养的心肌细胞分为：①Control组：细胞置CO2孵箱37℃,常规培养24h。②TG组：培养液中加1μMTG,作用24h;③PQS+TG组：160μg/mlPQS预处理24h后,按照②程序操作；④PERK敲低+TG组：以RNAi方法敲低心肌细胞PERK基因后,按照②程序操作：⑤随机双链RNA转染对照组+TG组(MOCK+TG):转染随机合成的25bp双链小RNA片段至心肌细胞后,按照②程序操作；⑥PERK过表达组：以PERK重组腺病毒感染24h;⑦PQS+PERK过表达组：培养液中加入终浓度为160μg/ml的PQS预处理24h后,按照⑥程序操作。以CCK-8法和流式细胞术分别检测细胞活性及凋亡率RT-PCR和Western blotting方法检测ERS标志分子GRP78、PERK、eIF2a、ATF4和CHOP的转录及翻译。
结果：与单纯TG处理组比较,敲低PERK表达及PQS预处理均可显著降低心肌细胞凋亡率,提高细胞比活力,降低ERS分子GRP78、ATF4及CHOP表达,降低PERK及eIF2a的磷酸化水平(P<0.05)。与Control组比较,单纯过表达PERK可升高心肌细胞凋亡率,降低心肌细胞比活力,升高ERS分子GRP78、ATF4及CHOP的翻译及转录水平,升高PERK及eIF2a磷酸化水平(P<0.05)；PQS预处理可显著改善过表达PERK导致的上述改变(P<0.05)。
结论：PQS预处理可产生类似PERK敲低对心肌细胞凋亡和细胞活性的效应,并且减轻过表达PERK导致的心肌细胞凋亡,机理可能与抑制ERS的PERK-eIF2a-ATF4-CHOP凋亡途径有关。
Ventricular remodeling (VR) after acute myocardial infarction (AMI) is a complicated pathological process, including thinning of the ventricular wall, dilatation of the ventricle and myocardial hypertrophy. The underlying mechanism of VR is not clear so far, though most researchers suppose that it involves apoptosis, hypertrophy of cardiomyocytes and fibrosis of the myocardial matrix. Endoplasmic reticulum stress (ERS) triggered by myocardial ischemia induces cardiomyocyte apoptosis, which presented as the up-regulation of ERS-induced apoptosis pathway glucose regulating protein78(GRP78), calreticulin (CRT), and C/EBP homologous protein (CHOP). Our previous study showed that CHOP-mediated ERS-related apoptosis was involved in rat myocardial hypertrophy induced by abdominal aortic constriction and in rat myocardial ischemia/reperfusion injury. However, whether the CHOP-mediated ERS-related apoptosis contributes to the VR after AMI remains to be studied.
Panax quinquefolium saponin (PQS) has been identified beneficial for VR after AMI, myocardial ischemia/reperfusion (I/R) injury, and hypoxia-reoxygenation (H/R) injury of cardiomyocytes in vitro. We found that PQS alleviates H/R injury and I/R injury by inhibiting excessive ERS in cardiomyocyte. Whether the effect of PQS on VR after AMI involves CHOP-mediated ERS-related apoptosis remains to be studied.
We established the AMI model by ligating the left anterior descending coronary artery of rats to determine the effects of PQS on LV remodeling after AMI, and explored its possible mechanism involving CHOP-mediated ERS-related apoptosis. The cardioprotective effects of PQS were studied on thapsigargin-treated cardiomyocytes from neonatal Sprague-Dawley (SD) rats to induce ERS-induced apoptosis. Recombinant adenovirus or RNAi were used to exogenous express or knockdown protein kinase R-like ER kinase (PERK), which aimed to explore the signal pathway of PQS inhibiting ERS related apoptosis in cardiomyocytes.
Part Ⅰ The improvement effect of PQS on VR after AMI
Objective:To study the effect of PQS on VR after AMI.
Methods:SD rats subjected to AMI were randomly treated with either driking water, PQS (50mg/kg/d,100mg/kg/d or200mg/kg/d) or taurine, an ERS inhibitor (300mg/kg/d) for4weeks. Left ventricle (LV) fractional shortening (FS), ejection fraction (EF) and structure were then evaluated using echocardiography. The hemodynamic parameters were obtained by carotid artery intubation, and the plasma BNP level was detected by BIOSITE Triage equipment. Myocardial infarct size was measured by Evans blue and2,3,5-triphenyhetrazolium chloride (TTC) staining. The hydroxyproline content in myocardium was determined using the colorimetric method.
Results:Compared with the AMI group, PQS treatment (50mg/kg/d,100mg/kg/d, and200mg/kg/d) significantly decreased LVESD and LVEDD and increased FS, EF, the mean arterial pressure, left ventricular systolic pressure, the maximal rates of rise and decline of left ventricular pressure (P<0.05) and significantly increased the left ventricular end-diastolic pressure and plasma BNP levels (P<0.05). A similar trend was observed between rats treated with taurine and rats treated with PQS200mg/kg/d. Conclusion:PQS improved the VR after AMI by attenuating cardiac structural changes, functional damage and fibrosis.
Part Ⅱ The inhibitory effects of PQS on ERS related apoptosis after AMI
Objective:To study the effect of PQS on ERS-related apoptosis after AMI.
Methods:Twenty-four hours after the surgery, the AMI rats were randomly divided into3groups as follows:AMI group, PQS200mg/kg/d group and taurine (300mg/kg/d) group. Another15rats underwent the same procedure except for the ligation of the coronary artery as the sham group. Cardiomyocyte apoptosis was detected using Terminal Deoxynucleotidyl Transferase Mediated dUTP Biotin Nick End Labeling (TUNEL). In addition, expression of ERS molecules in the non-infarcted myocardium was detected using Western blotting.
Results:Compared with the AMI group, PQS treatment (200mg/kg/d) significantly decreased the apoptosis index, the expression of GRP78, calreticulin (CRT), CHOP and Bax protein, as well as increased Bcl-2protein expression in non-infarcted myocardium. PQS200mg/kg/d treatment mimicked the results achieved from the taurine-treated rats. CHOP expression positively correlated with the apoptosis index of cardiomyocytes in the non-infarcted myocardium (r=0.797, P<0.01).
Conclusion:PQS treatment significantly attenuated apoptosis in the non-infarcted myocardium, which might be attributed to inhibiting CHOP-mediated ERS-related apoptosis.
Part Ⅲ The effect of PQS on decreasing cardiomyocytes apoptosis induced by thapsigargin
Objective:To study the effect of PQS on cardiomyocytes apoptosis induced by thapsigargin.
Methods:Primary cultured cardiomyocytes from neonatal SD rats were divided into6groups as follows:Control group, TG group (cells were treated with1μM TG for24h), PQS40μg/ml+TG group (cells were pretreated with40μg/ml PQS for24h and then treated with1μM TG for24h), PQS80μg/ml+TG group, PQS160μg/ml+TG group, taurine+TG group. Cell viability was detected by CCK-8. Apoptosis was detected by flow cytometry. Western blotting was used to detecte the expression of ERS molecules GRP78, PERK, CHOP and apoptosis related protein Bcl-2and Bax.
Results:Compared with TG group, PQS treatment (160μg/ml) significantly reduced the apoptosis and increased the cell viability (P<0.05). All the three different concentration of PQS significantly reduced the expression of GRP78, PERK, CHOP and Bax, and increased the expression of Bcl-2(P<0.05), in a dose dependent manner.
Conclusion:PQS160μg/ml attenuated cardiomyocyte apoptosis induced by thapsigargin through inhibiting excessive ERS.
Part Ⅳ The inhibitory effect of PQS on apoptosis through the PERK-eIF2a-ATF4-CHOP pathway
Objective:To explore the mechanism by which PQS inhibiting apoptosis induced by thapsigargin.
Methods:Primary cultured cardiomyocytes from neonatal SD rats were divided into6groups as follows:control group, TG group, PQS+TG group, Si-PERK+TG group, Random double-stranded RNA-transfected+TG group, PERK overexpression group (Ad-PERK), PQS+PERK overexpression group; Cell viability was detected by CCK-8. Apoptosis was detected by flow cytometry. RT-PCR and Western blotting was used to detecte the expression of ERS molecules including GRP78, PERK, eIF2a, and CHOP.
Results:Compared with TG group, both PERK knockdown and PQS pretreatment significantly reduced the rate of cardiomyocyte apoptosis, increased the cell viability, decreased the transcription and translation of ERS molecules GRP78, ATF4and CHOP (P<0.05) and decreased the phosphorylation of PERK and eIF2a (P<0.05). Compared with TG group, overexpression of PERK significantly increased the apoptosis rate, decreased the cell viability, and increased the transcription and translation of ERS molecules GRP78, ATF4and CHOP (P<0.05) and decreased the phosphorylation of PERK and eIF2a (P<0.05); PQS pretreatment significantly decreased the changes induced by PERK overexpression (P<0.05).
Conclusion:PQS pretreatment mimicked the effects of PERK knockdown, which would be related to the PERK--eIF2a-ATF4-CHOP apoptotic pathway of ERS.
引文
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