不同剂量卡维地洛对心衰大鼠心肌氧化应激和细胞凋亡的影响

目的 :探讨不同剂量卡维地洛 （CAR）对心肌梗死后大鼠心肌细胞凋亡的影响及 CAR治疗充血性心力衰竭（CHF）的作用机制。方法 :将雄性 Waistar大鼠前降支结扎 ,于术后 1周开始分别给予大剂量 CAR（HCAR组 ,6 0mg· kg- 1· d- 1 ）和小剂量 CAR（L CAR组 ,6 m g· kg- 1· d- 1 ）干预 7周 ,观察不同剂量 CAR对大鼠血流动力学参数、心肌细胞凋亡、心肌丙二醛 （MDA）含量和总抗氧化能力 （TAOC）的影响。结果 :CAR可改善心功能指标 ,降低心肌细胞凋亡指数及 MDA浓度 ,上调 TAOC水平 ,其中对心肌细胞凋亡指数 （HCAR组为 4 .6 %± 1.1% ,L CAR组为 8.0 %± 2 .0 % ）、TAOC（HCAR组为 1.92± 0 .2 0 U· mg- 1 ,L CAR组为 1.5 9± 0 .12 U· mg- 1 ）的影响以HCAR组明显。结论 :CAR可有效地减少心肌梗死后心肌细胞凋亡 ,防止 CHF的发生、发展 ,效果以大剂量明显 ,这可能与其维护心肌抗氧化防御系统有关     

不同剂量卡维地洛对心肌梗死后大鼠左室重构及心肌细胞凋亡的影响

目的观察不同剂量卡维地洛(CAR)对心肌梗死(MI)后大鼠左室重构及心肌细胞凋亡的影响。方法结扎大鼠冠状动脉前降支,随机分成三组:MI组,术后不用药,卡维地洛大剂量组(HCAR组),卡维地洛小剂量组(LCAR组),术后2d分别给予卡维地洛10 mg/kg和1.25 mg/kg。另外不手术不用药组为假手术组(SH组)。6周后测定左室重构指标及心肌细胞凋亡计数。结果卡维地洛用药组与MI组比较,左室重构明显改善,心肌细胞凋亡量明显减少,且有剂量依赖,大剂量组优于小剂量组。结论卡维地洛可改善AMI后大鼠的左室重构,并有剂量依赖性,减少心肌细胞凋亡可能是其重要因素之一。     

卡维地洛对心衰大鼠心肌细胞凋亡和Fas/Fas L基因表达的影响

目的 探讨卡维地洛对心力衰竭大鼠心肌凋亡的发生及Fas/Fas L基因及蛋白表达的影响.方法 取SD雄性大鼠,采用结扎前降支方法建立慢性心力衰竭模型,将存活动物随机分为假手术组、心力衰竭组、卡维地洛组.观察血流动力学变化、心肌细胞凋亡、Fas/Fas L基因表达情况.结果 较心力衰竭组相比较,卡维地洛可显著降低心率、LVEDP、±dp/dt(P<0.05);同假手术组相比较心力衰竭组凋亡指数、Fas/Fas L蛋白表达明显升高,Fas/GAPDH明显增加(P<0.05).而卡维地具有降低凋亡和Fas/Fas L基因及蛋白表达的作用(P>0.05).结论 慢性心力衰竭大鼠的心肌中Fas/Fas L有蛋白和基因水平上调,心肌凋亡指数升高;而卡维地洛可有效抑制有Fas/Fas L蛋白和基因水平的上调而降低心肌细胞凋亡的发生,卡维地洛可能通过抑制心肌细胞凋亡途径而起到保护心功能的作用.     

卡维地洛对心衰大鼠心肌细胞凋亡及NF-κB活性的影响

目的：探讨核因子-κB（NF-κB）活化与充血性心力衰竭大鼠心肌细胞凋亡的关系及卡维地洛（CAR）的作用机制。方法：观察雄性Waistar大鼠心肌梗死（MI）8周后的心肌细胞凋亡指数、心肌总抗氧化能力、丙二醛的浓度、Fas和FasL的mRNA水平、KB抑制蛋白-α（I-κB-α）表达及NF-κB的核结合活性的改变，并于MI后1周对大鼠进行7周的CAR和美托洛尔（MET）干预，观察CAR和MET对上述指标的影响。结果：MI后心肌细胞凋亡指数、丙二醛水平、Fas和FasL的mRNA水平、NF-κB活性增高，I-κB-α表达下调、总抗氧化能力下降（P〈0．05）。CAR和MET可不同程度地改善心功能指标（P〈0．05），CAR降低心肌细胞凋亡指数、丙二醛浓度、Fas和FasL表达及升高总抗氧化能力的效果优于MET，并上调I-κB-α表达、显著降低NF-κB活性（P〈0．05）。结论：氧化应激可激活NF-κB，启动Fas和FasL转录，介导心肌细胞凋亡，促进MI后充血性心力衰竭的发生、发展。CAR具有抗氧化作用，可通过抑制I-κB-α降解、降低心肌NF-κB活性，减少心肌细胞凋亡。     

卡维地洛对大鼠缺血再灌注心肌细胞凋亡及基因表达的影响

目的 :研究卡维地洛对缺血再灌注心肌细胞凋亡及bcl 2、bax基因表达的影响 ,探讨卡维地洛抑制缺血再灌注心肌细胞凋亡的可能分子机制。方法 :结扎Wistar大鼠左冠状动脉前降支 (LAD) ,建立大鼠缺血再灌注动物模型。 30只大鼠分 3组 (每组 10只 ) :卡维地洛组 (卡维地洛治疗 )、缺血再灌注组和假手术组。用Tunnel法检测心肌细胞凋亡 ,并用光学显微镜进行细胞计数 ,免疫组化和原位杂交法检测bcl 2、bax基因表达 ,并利用图像分析系统检测二者的平均光密度值 (A值 ) ,进行定量分析。结果 :心肌细胞凋亡数在缺血再灌注组、假手术组和卡维地洛组分别为 36 .8± 9.0、0 .2± 0 .1和 9.5± 3.0 ,各组间差异有统计学意义 (P <0 .0 1)。缺血再灌注组、假手术组和卡维地洛组的bcl 2mRNAA值分别为 0 .0 6± 0 .0 1、0 .0 8± 0 .0 1和 0 .0 9± 0 .0 1,bcl 2蛋白平均A值分别为0 .0 8± 0 .0 2、0 .14± 0 .0 1和 0 .15± 0 .0 3,卡维地洛组与缺血再灌注组相比差异无统计学意义 (P >0 .0 5 ) ;缺血再灌注组bax蛋白的平均A值为 0 .13± 0 .0 2 ,假手术组为 0 .0 7± 0 .0 1,卡维地洛组为 0 .0 6± 0 .0 1,卡维地洛组与缺血再灌注组相比差异有统计学意义 (P <0 .0 5 ) ,bcl 2 /bax蛋白比值在缺血再灌注组、假手术组和卡     

心力衰竭的心肌细胞凋亡及调控

细胞凋亡是人体组织细胞普遍存在的一种生理现象，细胞凋亡现象也存在于心力衰竭、心肌病、心律失常、冠脉疾病、Ｑ－Ｔ间期延长综合征，缺血再灌注损伤等心血管疾病中，心肌细胞凋亡参与了心力衰竭的敢心肌细胞数量的减少，加剧了心力衰竭。本文简述了心肌细胞凋亡在心力衰竭中的意义及其诱导因素，基因调控，以及对心力衰竭治疗的意义 。     

大鼠急性心肌梗死后心肌细胞凋亡和半胱天冬蛋白酶-3的表达及卡维地洛的防治作用

目的:研究大鼠急性心肌梗死后心肌细胞凋亡和半胱天冬蛋白酶-3(Caspase-3)的表达及卡维地洛的防治作用.方法:冠状动脉结扎术后24 h存活的雌性SD大鼠83只随机分为心肌梗死对照组(MI组,n=43)和卡维地洛[10 mg/(kg·d)]治疗组(C组,n=40)两组,另设假手术组(S组,n=27);最终血流动力学资料完整的上述各组大鼠数分别为11、13、9、15、10和10只.C组于术后24 h直接灌胃法给药.末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法(TUNEL)和脱氧核糖核酸(DNA)凝胶电泳检测心肌细胞凋亡.免疫组化方法和Western 印迹法检测Caspase-3的表达.结果:与S组相比,MI组的左心室收缩压(LVSP)和左心室内压最大上升和下降速率(±dp/dt)均显著降低(P<0.05～0.01),左心室舒张末压(LVEDP)均显著升高(P<0.05～0.01),且4 W时升高更为显著(P<0.01);梗死区或疤痕区、梗死边缘区和非梗死区的心肌细胞凋亡指数均显著升高(P<0.05～0.01),Caspase-3表达也均显著增高(P<0.05～0.01).与MI组相比,C组48 h的LVSP、±dp/dt和心率均显著降低(P<0.05～0.01),但LVEDP及上述各部位的心肌细胞凋亡指数和Caspase-3的表达均无显著变化;而C组4 W 的LVEDP及疤痕区、梗死边缘区的心肌细胞凋亡指数均显著降低(P<0.05～0.01),但LVSP、±dp/dt和Caspase-3的表达均无显著变化.结论:大鼠急性心肌梗死后,发生血流动力学和左心室功能异常,梗死区或疤痕区、梗死边缘区和非梗死区均有不同比例的心肌细胞发生凋亡,伴Caspase-3表达增高;卡维地洛长时间(4 W)治疗可改善心功能,阻止疤痕区和梗死边缘区心肌细胞凋亡的发生.     

应用细胞凋亡抑制因子评估心力衰竭患者心肌细胞凋亡水平

研究心力衰竭患者细胞凋亡抑制因子水平变化,评估衰竭心肌细胞凋亡状态。方法采取链霉亲和素－生物素ＥＬＩＳＡ法测定６０例心力衰竭患者和５２例正常对照组血清Ａｐｏ－１／Ｆａｓ,白细胞介素－６和肿瘤坏死因子α水平,并测定心力衰竭患者左室身血分数,了解ＥＦ变化与Ａｐｏ－１／Ｆａｓ间的关系。     

葶苈生脉方对充血性心力衰竭大鼠心肌细胞凋亡相关调控基因的影响

目的通过观察不同剂量葶苈生脉方对充血性心力衰竭(CHF)造模大鼠心肌细胞凋亡相关调控基因B细胞淋巴瘤/白血病-2基因(Bcl-2)、促凋亡基因Bax和凋亡蛋白酶Caspase-3表达的影响。方法 60只Wistar大鼠随机分为5组,每组12只。除假手术组外,其余4组手术造成腹主动脉狭窄,假手术组只分离腹主动脉,不结扎。5组均于造模4 w后开始给药。每日1次定量灌胃。5组均连续灌胃8 w。最后1次给药后,取少许心肌组织,运用流式细胞仪检测Bcl-2、Bax和Caspase-3蛋白表达的情况。结果与模型组比较,葶苈生脉方高、低剂量组Bcl-2蛋白表达免疫荧光指数(FI)值明显增加(P<0.05),Bax、Caspase-3蛋白表达FI值和Bax/Bcl-2比值明显降低(P<0.05)。结论葶苈生脉方可通过抑制心肌细胞凋亡,避免减少心肌细胞数量,恢复心肌细胞的功能,达到治疗CHF作用。     

心痛宁合剂对急性心肌梗死大鼠心肌细胞凋亡及凋亡相关基因表达的影响

目的观察心痛宁合剂对急性心肌梗死大鼠心肌细胞凋亡的影响。方法结扎大鼠冠状动脉复制急性心肌梗死模型,分为高、低剂量心痛宁合剂组、开搏通对照组、模型对照组,另设假手术对照组。用药1周后,取心肌切片,进行HE染色、免疫组织化学染色,观察心肌细胞凋亡。结果心痛宁合剂能有效的抑制心肌细胞凋亡,上调Bcl-2基因表达,下调Fas基因表达,与开搏通治疗比较,差异有统计学意义（P均〈0.05）。结论心痛宁合剂能够抑制大鼠心肌梗死的细胞凋亡,对治疗急性心肌梗死有良好疗效。     

急性下壁心肌梗死并心力衰竭的临床特征及预后

目的 :分析急性下壁心肌梗死 (AIMI)并心力衰竭 (心衰 )的临床特征及预后。方法 :记录 180例AIMI患者中并心衰者的临床特征及住院并发症 ,行常规 12导联心电图及右胸导联心电图 ,并与无心衰者比较。结果 :AIMI并心衰者 41例 (占 2 2 .8% )。并心衰组较无心衰组年龄大〔6 5 .3± 10 .8)岁∶ (6 1.1± 10 .1)岁〕、肌酸激酶 (CK)峰值高〔(2 70 0 .4± 2 0 87.7) IU / L∶ (1879.1± 16 0 3.1) IU / L〕,右室梗死 (31.7%∶ 5 .8% )及高度房室传导阻滞 (39.0 %∶ 17.3% )发生率高 ,胸前导联 V4～ 6 ST段压低为主者比例高 (5 6 .1%∶ 2 4.5 % ) ,住院病死率高(4 6 .3%∶ 17.3% )。 L ogistic回归分析显示 AIMI并心衰与 CK峰值、右室梗死、胸前导联 V4～ 6 ST段压低及死亡率独立相关 ,而与年龄及高度房室传导阻滞不相关。结论 :AIMI并心衰者胸前 V4～ 6 导联 ST段压低及右室梗死发生率高 ,CK峰值高。 AIMI并心衰住院病死率高 ,预后差 ,为一高危亚组。     

Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction

BACKGROUND:

Immune modulation by the Celacade system (Vasogen Inc, Canada) decreases mortality and hospitalization in human heart failure.

OBJECTIVES:

To study the effects of Celacade in rats on acute cytokine expression after coronary artery ligation, cardiac dimensions following myocardial infarction (MI), and systolic and diastolic function of cardiac muscle in MI.

METHODS:

Celacade treatment was administered 14 days before coronary artery ligation and monthly after the surgery. Cytokine expression in cardiac tissue was measured on days 1 and 7 by ELISA in sham rats and in rats with MI (with or without Celacade treatment). Echocardiograms were obtained serially for 16 weeks. Force and sarcomere length (SL) were measured by strain gauge and laser diffraction in isolated right ventricle trabeculas at 16 weeks. The inotropic effect of pacing on force was quantified as F_{5 Hz/0.5 Hz}. Diastolic dysfunction was quantified as the root mean square of spontaneous SL fluctuations.

RESULTS:

Celacade inhibited transforming growth factor beta-1 production in the infarct area on day 7 (191.6±22.6 pg/mg versus 275.4±30.1 pg/mg; P<0.05), but did not attenuate cardiac dilation in MI. Celacade restored positive inotropism of pacing in MI (F_{5 Hz/0.5 Hz} in Celacade, 219.1±46.7%; MI, 148.1±27.1% [P<0.05 compared with 211.4±37.9% in sham]). Celacade reduced diastolic dysfunction in MI (root mean square of spontaneous SL fluctuations: 121±15% and 143±19% with Celacade versus 184±19% and 190±26% without Celacade at 26°C and 36°C, respectively) compared with sham (100%; P<0.05).

CONCLUSIONS:

Celacade reduces the increase of transforming growth factor beta-1 expression during the acute stage of MI in rats, but does not prevent chronic cardiac dilation. Celacade restores the positive inotropic effect of increased pacing rate in trabeculas from rat right ventricles with large MIs and reduces diastolic dysfunction.     

Reduction in oxidative stress and modulation of heart failure subsequent to myocardial infarction in rats

BACKGROUND:

Patients surviving myocardial infarction (MI) are at a heightened risk for the development of congestive heart failure. This clinical syndrome has been associated with an antioxidant deficit and elevated oxidative stress in the myocardium. Effects of dietary vitamin E, a lipid-soluble antioxidant, on myocardial anti-oxidant enzyme activities, oxidative stress and hemodynamic function, were examined separately in the viable left ventricle (LV) and right ventricle (RV) of rats at 16 weeks post-MI.

METHODS AND RESULTS:

Animals were fed either a basal diet or a diet enriched with 1500 U of vitamin E/kg beginning two weeks before MI-inducing surgery and continued 16 weeks post-MI. In the MI animals on the basal diet, LV systolic pressure (LVSP) and RVSP were significantly depressed and LV end-diastolic pressure (LVEDP) and RVEDP were significantly elevated. These hemodynamic alterations were accompanied by clinical signs of heart failure including dyspnea, lethargy and cyanotic limbs. Supplementation of MI animals with dietary vitamin E resulted in complete normalization of RVSP and RVEDP. An increase in LVSP and a decrease in LVEDP was observed in the vitamin E-supplemented MI animals, although mild residual LV dysfunction remained. The myocardial enzymatic antioxidants catalase and glutathione peroxidase declined substantially in each of the ventricles of unsupplemented MI animals. Myocardial levels of vitamin E were reduced by 33% in the LV and no change was observed in the RV of the MI animals. Vitamin E-supplemented control animals and MI animals showed a significant increase in vitamin E levels in both ventricles. Myocardial oxidative stress, as assessed by lipid peroxidation and the ratio of reduced to oxidized glutathione, was significantly increased in each of the respective ventricles of untreated MI animals. Supplementation with dietary vitamin E resulted in a substantial increase in the myocardial activities of catalase and glutathione peroxidase in both the LV and RV. Furthermore, an increase in the ratio of reduced to oxidized glutathione concomitant with significantly less lipid peroxidation was also observed in each of the respective ventricles of MI animals supplemented with vitamin E. No overt clinical signs of heart failure were evident in these vitamin E-supplemented animals.

CONCLUSIONS:

An improved myocardial redox state and endogenous antioxidant reserve with vitamin E therapy, coupled with the modulation of the development of heart failure, lend strong support in favour of a pathophysiological role for increased oxidative stress in the pathogenesis of heart failure, at least in experimental animals. Association between an increase in oxidative stress and cardiac events in patients requires further examination.     

Short term triiodo-L-thyronine treatment inhibits cardiac myocyte apoptosis in border area after myocardial infarction in rats

Thyroid hormone (TH) levels decline after a myocardial infarction (MI). Treatment with TH has been shown to improve left ventricular (LV) function in MI and other cardiovascular diseases, but the mechanisms are not clear. We have previously shown that TH can prevent myocyte apoptosis via Akt signaling in cultured neonatal rat cardiomyocytes. In this study, the effects of triiodo-l-thyronine (T3) on LV function and myocyte apoptosis after MI was examined in rats. After surgery, MI rats were treated with T3 for 3 days. Compared with sham-operated rats, MI rats showed significantly increased LV chamber dimension during systole and decreased LV function. T3 treatment increased LV ± dP/dt but did not change LV chamber dimensions. MI rats also showed significantly increased myocyte apoptosis in the border area as assessed by DNA laddering and TUNEL assay. T3 treatment decreased the amount of DNA laddering, and reduced TUNEL positive myocytes in the border area, which was associated with phosphorylation of Akt at serine 473. These results suggest that T3 can protect myocytes against ischemia-induced apoptosis, which may be mediated by Akt signaling.     

Interleukin-10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction

Evidence has shown that pro-inflammatory cytokines, especially TNF-alpha, are involved in the inflammatory response in the remodelling process after myocardial infarction (MI). Although IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha, little is known about its role in post-MI left ventricular (LV) dysfunction. The aim of the present study was to investigate whether a therapy with rhIL-10 could be beneficial in an animal model of post-MI heart failure (HF). Rats with experimental MI were treated with rhIL-10 (75 microg/kg/d sc) starting directly after MI induction, and continuing for 4 weeks. Controls were untreated MI and sham-operated rats. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10, the ratio of TNF-alpha to IL-10, serum levels of MCP-1 as well as myocardial macrophage infiltration, were analyzed. Treatment with rhIL-10 significantly improved post-MI LV function (FS +127%;, dP/dt(max) +131%; LVEDP -36%). This effect was associated with a significant decrease in pro-inflammatory cytokine and chemokine levels (TNF-alpha, IL-6, MCP-1) and furthermore resulted in a reduced myocardial infiltration of macrophages.     

卡维地洛和培哚普利对急性心肌梗死后心功能改善的影响

目的 :观测卡维地洛和培哚普利对急性心肌梗死后心功能的影响。方法 :急性心梗后心功能不全住院患者 6 2例。随机分成 2组先分别给予卡维地洛及培哚普利治疗 3月 ,然后再联合治疗 3月后复查超声心动图测定左室功能。结果 :1单用卡维地洛或培哚普利均可显著降低左室收缩末期容积 （L VESV ） ,左室射血分数 （L VEF）明显增加 ,左室充盈早期血流传播速度 （L VFPS）明显加快。2两药联用后 L VESV,L VEF及 L VFPS较单用药组有显著性变化。结论 :卡维地洛和培哚普利可明显改善急性心梗后心功能不全患者左心功能     

一氧化氮对心肌梗死后心肌细胞凋亡的影响

目的研究不同浓度一氧化氮(NO)对心肌梗死后心肌组织抗氧化损伤能力(T-AOC)、bcl-2、bax蛋白表达及细胞凋亡的影响。方法新西兰兔32只,随机分为4组,(每组8只)。假手术组(Sham组)、心肌梗死组(MI组)、低剂量消心痛组(LISDN组,1.5mg·kg-1·d-1)、高剂量消心痛组(HISDN组,4.0mg·kg-1.d-1),皆3次/d灌胃。6周后取梗死灶边缘缺血心肌制作组织匀浆进行NO浓度(以NO2-/NO3-间接表示)、T-AOC测定,并作病理观察;免疫组化观察各组bcl-2、bax蛋白表达;TUNEL法比较其细胞凋亡程度。结果HISDN组心肌间质水肿,较多心肌纤维化与炎性细胞浸润,可见局灶性肌丝溶解,肌浆网明显扩张。而LISDN组病理改变较轻。与HISDN组比较,LISDN组心肌组织匀浆中NO浓度降低而T-AOC升高(P<0.05),bcl-2表达阳性率增高而bax表达率降低(P<0.01),细胞凋亡数低于HISDN组(P<0.01)。结论高浓度NO降低心肌梗死后心肌细胞T-AOC并增加细胞凋亡,而低浓度NO显示出更好保护作用。     

Acute myocardial infarction and congestive heart failure following a blunt chest trauma

 A 42-year-old man experienced chest discomfort after being struck by a low-speed flying object. Two weeks after the accident, the patient complained of severe shortness of breath accompanied by ankle edema. Chest X-ray indicated acute pulmonary edema and left ventricular enlargement. There were Q waves and flat T waves in the precordial ECG leads. Echocardiography revealed dyskinesis in the interventricular septum, hypokinesis in the anterior left ventricular wall, and severe impairment of left ventricular function. A coronary angiogram showed 90% stenosis of the proximal left descending coronary artery. Subsequent medical therapy with diuretics and enalapril led to significant improvement in ventricular function and the patient's symptoms. We conclude that a mild blunt chest trauma can cause myocardial infarction and severe congestive heart failure. Careful investigations into myocardial ischemia or infarction and a close follow-up should be conducted in all patients presenting with a blunt chest trauma. Received: April 22, 2002 / Accepted: August 2, 2002 Correspondence to L. Wang