阿托伐他汀下调大鼠心肌梗死后线粒体融合素2表达和细胞凋亡简

 目的 研究阿托伐他汀通过下调线粒体融合素2表达抑制大鼠心肌梗死后细胞凋亡。 方法 雄性SD大鼠48只,随机分为假手术组（Sham）,心肌梗死组（MI）,阿托伐他汀1组（Statin 1）和2组（Statin 2）,每组12只。分别于术前7天开始每日灌胃,给予阿托伐他汀10和40mg/kg,MI组以蒸馏水灌胃,随后结扎大鼠前降支建立心肌梗死模型。术后24h用TUNEL法检测心肌细胞凋亡,免疫组化法检测线粒体融合素2表达,免疫印迹法检测磷酸化蛋白激酶B（p-Akt）表达。 结果 与Sham组相比,MI组心肌细胞凋亡显著增加,线粒体融合素2表达显著增加,p-Akt表达显著下降（p＜0.01）;与MI组相比,Statin 1和2组心肌细胞凋亡和线粒体融合素2表达均显著降低（p＜0.05）,而p-Akt表达显著增高（p＜0.05）,且Statin 2组较1组变化更显著（p＜0.05）。结论 阿托伐他汀可抑制大鼠心肌梗死后的细胞凋亡,其作用可能与下调线粒体融合素2表达有关。     

阿托伐他汀联合丙泊酚治疗能够抑制NLRP3炎症小体缓解大鼠心肌缺血再灌注损伤

目的 探讨阿托伐他汀与丙泊酚联合治疗在大鼠心肌缺血再灌注损伤中的作用机制及其与NLRP3炎症小体之间的关系。方法 构建心肌细胞缺血再灌注模型;将大鼠随机分为假手术组（Sham）、模型组（MIRI）、阿托伐他汀组（Atorvastatin）、丙泊酚组（Propofol）和阿托伐他汀与丙泊酚联合组（Atorvastatin+Propofol）。应用TTC染色法检测各组大鼠心肌损伤面积;应用TUNEL染色法检测心肌细胞的凋亡情况;免疫荧光法检测ROS的表达水平;ELISA法检测心肌细胞中TNF-α、IL-6、IL-1β和IL-18的表达情况;应用Western blot法检测NLRP3、Caspase-1、IL-1β及GSDMD-N的变化。结果 与模型组相比,阿托伐他汀和丙泊酚联合治疗组中大鼠的心肌梗死面积降低显著降低（P<0.05）;心肌细胞的凋亡率显著降低（P<0.05）;ROS的水平显著下降（P<0.05）;TNF-α、IL-6、IL-1β和IL-18的表达明显下降（P<0.05）以及NLRP3、Caspase-1、IL-1β及GSDMD-N等蛋白的水平显著降低（P<0.05）。结论 阿托伐他汀与丙泊酚联合治疗能够降低心肌细胞的凋亡、氧化应激反应和炎症反应,其机制与下调NLRP3炎症小体及其相关的蛋白表达有关。     

急性心肌梗死大鼠钙调蛋白的改变及卡维地洛的干预作用

目的：研究急性心肌梗死（AMI）后心力衰竭大鼠心肌钙调蛋白肌质网Ca2+-ATP酶（SERCA）和受磷蛋白（PLB)的变化及卡维地洛对其干预作用。 方法： 选取AMI术后成活的雄性SD大鼠随机分为AMI组、卡维地洛组两组。给药6周后观察血流动力学参数、心室重构指标及钙调蛋白SERCA、PLB的蛋白和mRNA表达。另设正常对照组及假手术组。 结果： AMI组左室舒张末压（LVEDP）、各心室重量均显著大于假手术组，左室内压最大收缩和舒张速率（±dp/dt）显著低于假手术组；SERCA蛋白和mRNA表达显著低于假手术组（P<0.01），PLB蛋白和mRNA表达高于假手术组（P<0.01）。卡维地洛组的LVEDP、心室重量均显著低于AMI组，±dp/dt显著高于AMI组；卡维地洛治疗使SERCA蛋白和mRNA表达明显升高（P<0.05），但未能改变PLB蛋白和mRNA水平(P>0.05）。 结论： 急性心肌梗死后心力衰竭中钙调蛋白SERCA和PLB的变化可能是心肌收缩功能失调的重要机制；卡维地洛能有效地抑制大鼠AMI后心室重构并改善血流动力学，其分子机制可能与钙调蛋白SERCA含量正常化有关。     

氟伐他汀对大鼠心肌梗死后左室重构及caspase-3表达的影响

目的：观察氟伐他汀对大鼠心肌梗死后左室重构及凋亡基因caspase-3的影响。 方法： 复制心肌梗死动物模型，实验分为4组，Ⅰ组假手术组，Ⅱ组假手术+氟伐他汀组，Ⅲ组模型组，Ⅳ组模型+氟伐他汀组。Ⅱ和Ⅳ组术后给氟伐他汀10 mg·kg^-1·d^-1共4周，观察左室结构及心动超声变化，心肌羟脯氨酸含量及caspase-3表达。 结果： Ⅳ组心肌超微结构和左室重构指标改善程度明显高于Ⅲ组，羟脯氨酸含量及免疫组化caspase-3阳性细胞明显少于Ⅲ组（P<0.05），RT-PCR caspase-3 mRNA表达也明显少于Ⅲ组（P<0.05）。 结论： 氟伐他汀能改善大鼠心梗后左室重构，并下调凋亡基因caspase-3表达，抑制细胞凋亡。     

阿托伐他汀对心肌梗死大鼠心肌细胞核内FoxO3a表达的影响

目的探讨阿托伐他汀对大鼠心肌梗死(myocardial infarction,MI)后心肌细胞核内FoxO3a表达和心室重构的影响。方法建立大鼠MI模型,24 h后存活大鼠随机分成MI组(n=8)、阿托伐他汀10 mg组[10 mg/(kg.d),Ato组,n=8],同时另设假手术组(Sham组,n=10)。4周后观察左心室质量指数(left ventricular mass index,LVMI),免疫组化染色和RT-PCR检测FoxO3a在左心室非梗死区(non-infarction zone,NIZ)心肌细胞核内蛋白质和mRNA表达水平,流式细胞技术(flow cytometry,FCM)检测FoxO3a蛋白在NIZ心肌细胞核内表达含量。SAS9.1统计软件分析数据。结果 MI组与Sham组相比,LVMI显著增加(P<0.05);左室心肌非梗死区FoxO3a mRNA、FoxO3a蛋白表达(免疫组化)、FCM检测心肌细胞核内蛋白表达量表达均降低(P<0.05)。与MI组相比,Ato组LVMI显著下降(P<0.05);但高于Sham组(P<0.05);与MI组比较Ato组左室心肌非梗死区FoxO3a mRNA、Fox-O3a蛋白表达(免疫组化)、FCM检测心肌细胞核内蛋白表达量表达均显著增高(P<0.05);但低于Sham组(P<0.05)。结论阿托伐他汀能够有效地改善MI后心室重构,机制可能与上调细胞核内FoxO3a表达量有关。     

阿托伐他汀对自发性高血压大鼠HMG-CoA还原酶表达的影响

 目的：评价阿托伐他汀对自发性高血压大鼠（SHR）HMG-CoA还原酶表达的影响。 方法：12只8周龄的SHR随机分为蒸馏水饲养组（SHR_DW组，n＝6）与阿托伐他汀治疗组（SHR_ATV组，n＝6），并以6只同周龄的正常血压大鼠（WKY）作为对照（WKY组，n＝6）。采用RT-PCR与Western blotting法分别检测HMG-CoA还原酶的mRNA及蛋白表达。同时检测血压与血脂。 结果：给药10周后，SHR_ATV组收缩压显著低于治疗前及SHR_DW组（P<0.05），其血清TC、TG、LDL-C及HDL-C的水平与SHR_DW组及WKY组相比，也明显降低（P<0.05）；SHR_ATV组HMG-CoA还原酶mRNA的表达水平在给药10周后显著低于WKY组及SHR_DW组（P<0.05），其蛋白表达水平同样出现类似的结果。 结论：阿托伐他汀能够下调HMG-CoA还原酶的mRNA及蛋白表达水平，不仅使SHR的血脂降低，在某种程度上，还可能与其血压的下降有关。     

阿托伐他汀影响自发性高血压大鼠血压的机制探讨

目的：探讨阿托伐他汀控制自发性高血压大鼠（SHR）高血压的机制，研究阿托伐他汀对SHR血浆内皮素-1（ET-1）和主动脉一氧化氮合酶（NOS）的影响，以及对SHR的主动脉平滑肌细胞（ASMC）凋亡和P27蛋白表达的影响。 方法： 选用8周龄SHR 12只，随机分为阿托伐他汀治疗组（ATV组, n=6）和SHR组（n=6），并以同周龄WKY（n=6）作为对照。ATV组给以阿托伐他汀（50 mg·kg-1·d-1）灌胃。10周后观察3组大鼠血压、血清总胆固醇（TC）、总甘油三酯（TG）含量变化，血浆ET-1和主动脉NOS活性的改变，以及TUNEL法检测ASMC凋亡率，测定动脉ASMC P27蛋白表达。 结果： 阿托伐他汀给药10周后，ATV组动脉收缩压显著低于SHR组［（134.17±3.60）mmHg vs （173.33±3.78）mmHg, P<0.01］；ATV组血清TC和TG浓度均显著低于SHR组（P<0.01, P<0.01）。同时，阿托伐他汀显著降低SHR血浆ET-1水平［（130.04±40.07）ng/L vs （196.74±59.69）ng/L，P<0.05］和增加SHR主动脉NOS活性［(0.189±0.040）kU/g protein vs （0.124±0.057）kU/g protein，P<0.01］；ATV组ASMC凋亡率显著高于SHR组（16.94%±3.08% vs 9.01%±2.36%, P<0.01）；ATV组ASMC P27蛋白表达阳性率显著高于WKY大鼠（33.02%±5.01% vs 24.25%±4.41%, P<0.05），而SHR组该指标明显低于WKY大鼠（16.08%±7.09% vs 24.25%±4.41%, P<0.05）。 结论： 阿托伐他汀控制SHR血压增高，其机制可能与降低SHR的血浆ET-1水平和增高主动脉NOS活性，以及增高ASMC凋亡率和P27蛋白表达阳性率有关。     

阿托伐他汀通过调节钠-钙交换体改善心力衰竭大鼠心脏功能

目的:探讨阿托伐他汀对心力衰竭大鼠心脏功能及心肌细胞钠-钙交换体表达的影响。方法:结扎大鼠冠状动脉左前降支8周,制备心肌梗死后心力衰竭模型。随机分3组,即假手术组、心力衰竭组与阿托伐他汀治疗组,分别于结扎后第2天给予安慰剂或阿托伐他汀治疗。8周后测定大鼠心脏功能及钠-钙交换体蛋白表达水平。培养原代乳鼠心肌细胞,通过缺氧模型分析阿托伐他汀对细胞内钙水平的影响。结果:阿托伐他汀治疗组较心衰组BNP水平降低,左室舒张末内径缩小,左室短轴缩短率升高。阿托伐他汀治疗明显降低心力衰竭时钠-钙交换体蛋白表达量,抑制缺氧诱导细胞内钙水平增加。结论:阿托伐他汀治疗改善心功能,可能与影响心力衰竭心肌细胞钠-钙交换体的表达及功能有关。     

阿托伐他汀下调大鼠心肌梗死后线粒体融合素2表达和细胞凋亡

目的研究阿托伐他汀通过下调线粒体融合素2表达抑制大鼠心肌梗死后细胞凋亡。方法雄性SD大鼠48只,随机分为假手术组(sham),心肌梗死组(MI),阿托伐他汀1组(statin 1)和2组(statin 2),每组12只。分别于术前7天开始每日灌胃,给予阿托伐他汀10和40 mg/kg,MI组以蒸馏水灌胃,随后结扎大鼠前降支建立心肌梗死模型。术后24 h用TUNEL法检测心肌细胞凋亡,免疫组化法检测线粒体融合素2表达,免疫印迹法检测磷酸化蛋白激酶B(p-Akt)表达。结果与sham组相比,MI组心肌细胞凋亡显著增加,线粒体融合素2表达显著增加,p-Akt表达显著下降(P0.01);与MI组相比,statin 1和2组心肌细胞凋亡和线粒体融合素2表达均显著降低(P0.05),而p-Akt表达显著增高(P0.05),且statin 2组较1组变化更显著(P0.05)。结论阿托伐他汀可抑制大鼠心肌梗死后的细胞凋亡,其作用可能与下调线粒体融合素2表达有关。     

阿托伐他汀对自发性高血压大鼠血压、循环和心肌血管紧张素Ⅱ水平的影响

目的：观察阿托伐他汀对自发性高血压大鼠（SHR）血压、循环和心肌血管紧张素Ⅱ(Ang Ⅱ)水平的影响。 方法: 24只SHR随机分为4组（每组6只）：SHR对照组、阿托伐他汀50 mg组、阿托伐他汀10 mg组和缬沙坦组, 6只WKY大鼠作为正常血压对照组（WKY组）。给药前和给药后每两周测量大鼠尾动脉收缩压（SBP）。测定血清脂质及血浆和心肌血管紧张素Ⅱ（AngⅡ）水平。 结果: SHR各组SBP于给药前无显著差异（P>0.05），但均显著高于WKY组（P<0.01）；给药后第4、6周,阿托伐他汀50 mg组SBP明显低于SHR对照组（P<0.01）,10 mg组则不明显；缬沙坦组自给药后第2周，SBP进行性下降（P<0.01）。SHR对照组与WKY组血脂各项指标无显著差异（P>0.05）；阿托伐他汀50 mg组TC、TG及LDL-C水平明显低于SHR对照组（P<0.05，P<0.01），10mg组仅LDL-C水平明显下低于SHR对照组（P<0.05）。SHR对照组血浆AngⅡ浓度无明显差异，但心肌AngⅡ浓度明显高于WKY组（P<0.05）；给药6周后，阿托伐他汀各剂量组和缬沙坦组血浆AngⅡ浓度显著高于SHR对照组（均P<0.01），而心肌AngⅡ浓度在阿托伐他汀50 mg组和缬沙坦组明显低于SHR对照组（P<0.05）。 结论: 阿托伐他汀能降低SHR的血压，机制可能与降低心肌AngⅡ浓度含量有关。     

Administration of pigment epithelium-derived factor inhibits left ventricular remodeling and improves cardiac function in rats with acute myocardial infarction

Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-week-old Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 μg PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-β and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.     

Enhancing efficacy of stem cell transplantation to the heart with a PEGylated fibrin biomatrix

Bone marrow-derived mononuclear cell (BMNC) transplantation provides the possibility of rescue or regeneration of myocardium lost during acute myocardial infarction (AMI). The extensive death of transplanted cells and the lack of sustained engraftment may limit its application. We investigated whether delivery of BMNCs by an injectable PEGylated fibrin biomatrix that covalently binds hepatocyte growth factor (HGF) would enhance the rate of cell engraftment and improve cardiac function. Balb/C female mice with AMI secondary to left anterior descending coronary ligation were randomly assigned to one of six groups: the Saline control group (n = 8) received a myocardial injection of saline (50 microL); the Cell group (n = 10) received a myocardial injection in the peri-infarct and infarct zones consisting of 500,000 murine BMNCs suspended in 50 microL saline; and the Biomatrix + HGF (n = 9) and Biomatrix + HGF + Cell (n = 9) group hearts received the HGF-loaded injectable biomatrix (identical volume) with or without entrapped BMNCs. Control groups consisting of the biomatrix alone (n = 9) and Biomatrix + Cells (n = 9) without HGF were also included for comparison. The left ventricular (LV) function was measured by echocardiography at days 14 and 28 post-MI. All animals were euthanized 4 weeks after AMI and transplantation for evaluation of angiogenesis, apoptosis, and fibrosis by immunohistochemistry. Cell prevalence rate at 4 weeks increased 15-fold in hearts receiving the Biomatrix + HGF + Cell delivery (p < 0.01), which was accompanied by the lowest levels of apoptosis and the highest LV function recovery among the treated groups.     

氟伐他汀对大鼠心肌梗死后左室功能、肌球蛋白重链基因表达及胶原重建的影响

目的：观察羟甲基戊二酰辅酶A还原酶抑制剂氟伐他汀对大鼠急性心肌梗死(AMI)后左室功能、肌球蛋白重链（α、β MHC）基因转录mRNA表达及胶原重建的影响。 方法： 雌性SD大鼠AMI术后6 h随机分为：①AMI对照组；②氟伐他汀组；③假手术组。 直接灌胃给药8周后行高频多普勒超声、血流动力学、左室心肌α、β MHC的mRNA、非梗死区胶原容积分数(CVF)及Ⅰ/Ⅲ胶原的免疫组化测定。 结果： AMI组E峰、E峰减速度、E/A、左室舒张末压(LVEDP)、β MHC mRNA、非梗死区CVF及Ⅰ/Ⅲ胶原比值明显高于假手术组，左室短轴速短率（FS）、射血分数（EF）、平均动脉压（MAP）和α MHC mRNA 显著低于假手术组。氟伐他汀组的E峰、E峰减速度、E/A、LVEDP、β MHC mRNA、非梗死区CVF及I/Ⅲ胶原比值明显低于AMI组，FS、EF、MAP和α MHC mRNA显著高于AMI组。 结论： 氟伐他汀对心梗后左室功能、肌球蛋白链基因mRNA表达及胶原重建可产生有益的影响。     

糖尿病在糖尿病大鼠心肌梗死后心力衰竭形成中的效应

目的： 评估糖尿病在链脲霉素（STZ）诱导的血糖不加控制的糖尿病大鼠急性心肌梗死（AMI）后心力衰竭(HF)形成中的效应。方法：所有SD大鼠随机分组,糖尿病组经腹腔内注射STZ（65mg/kg）诱导糖尿病,70 d后所有AMI组结扎冠状动脉左前降支建立AMI模型。确定AMI前后各时点观察大鼠的生存率,心肌超微结构的变化,进行血流动力学分析、心肌纤维化测定及左心肥厚的评估。结果：结扎左冠状动脉前降支后,糖尿病大鼠的左心功能恶化及左室重构的速度均较非糖尿病大鼠显著。在早期阶段,糖尿病与非糖尿病大鼠心肌纤维化相似,而1月后却出现显著差别。结论：糖尿病大鼠AMI后心力衰竭进展明显加速。     

阿托伐他汀对急性心肌梗死大鼠内皮微颗粒及心肌细胞凋亡的影响

目的:探讨阿托伐他汀(atorvastatin,AT)对大鼠急性心肌梗死早期内皮微颗粒(endothial microparticles,EMP)及心肌细胞凋亡的影响。方法:将24只雄性SD大鼠随机分为假手术组(sham组)、心肌梗死组(MI组)和阿托伐他汀心肌梗死组(MI+AT组),每组8只。采用冠状动脉结扎制作急性心肌梗死大鼠模型。分别在造模后2 h和24 h采外周血检测肌酸激酶同工酶(creatine kinase-MB,CK-MB)、心肌肌钙蛋白T(cardiac troponin T,c Tn T)和EMP,其中循环EMP用流式细胞术检测。通过TUNEL检测心肌细胞凋亡情况。结果:造模后2 h,MI组大鼠的CK-MB表达水平较sham组大鼠显著升高(P0.05);MI组及MI+AT组大鼠EMP表达水平及心肌细胞凋亡率上升,显著高于sham组(P0.05)。造模后24 h,MI组大鼠EMP表达水平显著高于sham组(P0.05);MI+AT组大鼠CK-MB、c Tn T、EMP表达水平及心肌细胞凋亡率较MI组显著降低(P0.05)。此外,MI组大鼠的CKMB表达水平在造模后24 h较造模后2 h显著升高(P0.05);MI+AT大鼠CK-MB、c Tn T和EMP表达水平在造模后24 h较2 h显著下降(P0.05)。结论:AT可降低大鼠急性心肌梗死时的EMP水平和心肌细胞凋亡率,提示AT对内皮功能有保护作用。     

Sdc1 Overexpression Inhibits the p38 MAPK Pathway and Lessens Fibrotic Ventricular Remodeling in MI Rats

Expression of the proteoglycan syndecan-1 (Sdc1) is increased in rats with myocardial infarction (MI). This study investigated the effects of Sdc1 overexpression on ventricular remodeling and cardiac function in MI and explored the possible mechanism through in vivo transfection of rats with recombinant adenovirus-carrying rat Sdc1 cDNA. Sprague–Dawley rats (n?=?48) underwent intramyocardial injection in the marginal zone of the infarcted area immediately after ligation of the left anterior descending artery. The rats were divided into four groups according to the solution injected: MI Ad-GFP-Sdc1 transfection group, MI Ad-GFP control group, MI saline group, and sham operation group. Cardiac function and collagen expression of each group were examined, and the roles of inflammation, apoptosis, and p38 MAKP signal transduction pathway were investigated. Compared with the rats in the sham operation group, ventricular weight and collagen content increased in MI rats, and cardiac function declined. Substantial inflammatory cell infiltration was seen in the marginal zone of the infarction area, and a great number of myocardial cells were apoptotic. The p38 MAPK signaling pathway was clearly activated. Rats in the MI Ad-GFP-Sdc1 transfection group showed decreased ventricular weight, reduced collagen synthesis, and significant improvement of ventricular remodeling and cardiac function. Post-MI inflammatory cell infiltration and apoptosis was reduced, and the p38 MAPK signaling pathway was inhibited. Overexpression of Sdc1 can improve post-MI ventricular remodeling, and it is possible that the improvement is achieved through reducing apoptosis and suppressing inflammatory response and through the p38 MAPK signal transduction pathway.     

Swimming exercise training prior to acute myocardial infarction attenuates left ventricular remodeling and improves left ventricular function in rats

The effect of exercise training prior to acute myocardial infarction (AMI) on left ventricular (LV) remodeling is poorly understood. This study investigated the protective effect of 3 weeks of swimming exercise training prior to AMI on cardiac morphology and function. Male Sprague-Dawley rats (n = 35) were randomly assigned to 3 groups: swimming training (n = 14, 90 min, 5 days/wk, 3 wk), sedentary (n =14), and controls (n = 7, no exercise, no MI). At the end of the training/sedentary period, rats were subjected to AMI (ExMI and SedMI) induced by surgical ligation of the left coronary artery. Thereafter, the rats remained sedentary for a 4-wk recovery period. Trans-thoracic echocardiography was performed in each group at the end of the exercise/sedentary period (pre-AMI), 24 hr after AMI, and following recovery (4 wk after AMI). No differences were observed in LV dimensions and function pre-AMI among the 3 groups; however, LV-end systolic diameter (LVESD) and LV-end systolic area (LVES-area) were significantly lower in the prior trained rats, 24 hr post-AMI with no additional change 4 wk post-AMI, during remodeling. Both LV-shortening fraction (SF%) and fractional area change (FAC%) were higher in the trained animals 4 wk post-AMI (39+/-12% vs 23+/-8%; p 0.002, and 48+/-14% vs. 38+/-9%; p 0.07, respectively). In conclusion, 3 wk of swimming exercise training prior to AMI significantly attenuated LV remodeling and improved LV function, despite no changes in LV dimensions or systolic function at the end of the exercise session. The data suggest that even a short-term training period is sufficient to induce cardiac protection.