氧化苦参碱心脏保护作用的研究进展

氧化苦参碱对心脏具有正性肌力、负性频率和负性自律性的作用,因此具有广谱抗心律失常作用。氧化苦参碱对冠脉狭窄缺血、缺血再灌注以及异丙肾上腺素、阿霉素、感染和免疫引起的心肌损伤都有保护作用,并能阻滞心肌肥大和纤维化发生发展。氧化苦参碱心脏保护作用的基本机制是其抗氧化、抗炎和免疫抑制以及抑制盐皮质激素（醛固酮）受体的表达,产生心肌保护作用。即通过激活Nrf2/HO-1信号通路和抑制转化生长因子（TGF）-β1及I型TGF-β1受体的表达,从而抑制下游的JAK/STAT、MAPK/Smad2/3和Notch的信号通路的机制,减少心肌细胞凋亡,减轻心肌损伤和抑制胶原合成,产生抑制心肌肥大和纤维化的作用。     

氧化苦参碱的肾脏保护作用及其机制的研究进展

氧化苦参碱具有抗肾缺血再灌注损伤、抗内毒素性肾损伤、抗四氯化碳致慢性肾损伤、抗阿霉素肾病、抗输尿管梗阻大鼠肾间质纤维化和抗高糖、高脂诱导的肾脏纤维化的作用。氧化苦参碱肾脏保护作用的作用机制是抗氧化、抗炎、降血糖、调血脂作用,抑制活性氧(ROS)/TLR4、PERK/ATF4/CHOP、JAK2/STATs、TGF-β1/Smads和NF-κB/TNF-α信号通路,减轻肾损伤炎症反应和细胞外基质沉积,阻滞肾损伤和纤维化。     

苦参碱防治肾病的药理作用及其机制的研究进展

苦参碱具有抗内毒素性肾损伤、抗化疗药肾损伤、抗免疫性肾损伤、抗尿酸性肾病、抗输尿管梗阻大鼠肾间质纤维化和抗糖尿病肾病的作用。苦参碱肾脏保护作用的机制可能是下调脂多糖识别受体的表达、抑制JAK/STAT通路、抑制PI3K/AKT/mTOR通路和抑制ERK1/2通路,从而阻断TGF-β1/Smad和NF-κB炎性信号通路,减轻肾脏炎症反应和细胞外基质沉积,产生延缓肾脏纤维化的作用。     

JAK-STAT信号通路与心脏疾病研究进展

细胞因子受体介导JAK-STAT信号传导途径是目前细胞因子研究领域的热点。近年来发现,JAK—STAT通路与心肌肥大、心力衰竭、心肌缺血引起的心功能障碍以及缺血预处理诱导的心肌保护都与这一信号通路密切相关,为心脏疾病的分子机制研究提供了借鉴。     

苦参碱对阿霉素诱导大鼠心肌损伤的保护作用及其机制研究

目的研究苦参碱对阿霉素诱导大鼠心肌损伤的保护作用及其机制。方法 SD大鼠随机分为对照组、模型组和苦参碱25、50、100 mg/kg组,每组各20只。模型组大鼠ip注射用阿霉素2.5 mg/kg,1次/周,连续给药6周,累积剂量15 mg/kg,建立心肌损伤模型。对照组ip等量生理盐水。苦参碱组造模前2 d ip注射用苦参碱25、50、100 mg/kg,连续给药5 d。观察大鼠心肌细胞病理学,采用酶联免疫吸附法检测大鼠血清线粒体偶联因子CF6水平,应用分光光度法测定Na~+-K~+-ATP酶、Ca2~+-ATP酶活力,采用试剂盒检测谷胱甘肽过氧化物酶(GSH-px)、总超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量。结果苦参碱各组心肌组织肿胀,肌束间、间质有灶性出血现象显著减轻。与模型组比较,苦参碱各组血清CF6水平显著降低(P0.05);线粒体Na~+-K~+-ATP酶、Ca2~+-ATP酶活性显著升高(P0.05);心肌组织GSH-px活性及SOD活力升高,MDA含量显著降低(P0.05)。结论苦参碱能保护阿霉素引起的大鼠心肌损伤,其作用机制与改善线粒体ATP酶活性、降低线粒体偶联因子6水平、减轻氧化应激水平有关。     

红景天苷心脏保护药理作用的研究进展

红景天苷通过促进心肌细胞肌浆网释放Ca²⁺,增强心肌收缩力,又可上调肌浆网钙泵的表达和下调钙调神经磷酸酶的表达,促进Ca²⁺返回肌浆网,阻滞钙超载引起的心肌损伤,有利于改善心功能。红景天苷通过抗氧化和抗炎作用,抑制心脏脂质过氧化反应,提高心脏组织的抗氧化酶活性,抑制炎性细胞因子表达和线粒体通透性转换孔开放,阻滞心肌细胞凋亡;也可通过上调缺氧诱导因子和血管内皮生长因子表达,促进缺血心肌血管形成,改善心肌缺血;还通过上调PGC-1α-NRF-1/NRF-2表达的通路,改善心肌线粒体呼吸功能,最终产生心脏保护作用。基于上述作用机制,红景天苷可对抗缺氧、缺血、缺血再灌注、力竭运动、化学品、生物毒素等引起的心脏损伤。     

黄芪有效活性成分防治心肌纤维化的研究现状北大核心CSCD

以胶原纤维过量积聚、胶原含量过度升高和胶原容积显著增高为主要病理改变的心肌纤维化是多种心血管疾病发展到一定阶段的共同病理表现,其严重影响心功能。但是现代医学对心肌纤维化的治疗手段缺乏,而近年来关于黄芪防治心肌纤维化取得了诸多实验研究,且效果显著。本文从调节磷脂酰肌醇3-激酶/蛋白激酶/糖原合酶激酶-3β(PI3K/Akt/GSK3-β)/Snail信号通路、转化生长因子-β1(TGF-β1)/Smads信号通路、抗氧化应激反应、调节免疫炎症损伤及抑制心肌细胞凋亡、纠正能量代谢异常、抗铁死亡等方面就黄芪有效活性成分防治心肌纤维化的研究现状进行综述。     

JAK ERK1/2两通路交互作用干预对缺血再灌注心肌p-STAT3和肿瘤坏死因子-α表达的影响

目的研究Janus激酶/信号转导和转录激活子(JAK/STAT)通路和细胞外信号调节激酶1/2(ERK1/2)信号转导通路交互作用对缺血再灌注损伤所致大鼠心肌组织p-STAT3及肿瘤坏死因子(TNF)-α蛋白含量的影响。方法采用Langendorff离体工作心脏灌注模型,大鼠随机分为健康对照组、缺血再灌注组、JAK抑制剂组、ERK1/2抑制剂组、JAK、ERK1/2两通路交互作用组。采用Western印迹法测定心肌p-STAT3蛋白含量,酶联免疫吸附测定法(ELISA)检测试剂盒检测TNF-α蛋白含量。结果与健康对照组相比,心肌组织p-STAT3含量及TNF-α蛋白含量在缺血再灌注组显著升高(P<0.01)。JAK抑制剂组及交互作用组处理后p-STAT3蛋白含量、TNF-α蛋白含量与缺血再灌注组相比明显下降(P<0.01,P<0.05);且2组间比较差异有统计学意义(P<0.05)。而ERK1/2抑制剂组处理后p-STAT3、TNF-α蛋白含量与缺血再灌注组差异无统计学意义(P>0.05)。结论缺血再灌注心肌损伤可使p-STAT3蛋白含量、TNF-α蛋白含量明显升高;抑制JAK/STAT信号转导通路可使其下游蛋白p-STAT3含量及TNF-α蛋白含量明显降低,且同时抑制ERK1/2信号通路对其心肌保护有明显抑制作用。     

TGF-β/Smads信号通路在心力衰竭心肌纤维化中的作用及中医药干预研究现状

在心力衰竭(HF)进展过程中,转化生长因子-β(TGF-β)/Smads信号通路的异常转导是HF心肌纤维化(MF)的重要机制。TGF-β是MF的关键因子,在HF MF过程中处于过度表达状态。Smads是TGF-β下游的主要效应因子,TGF-β/Smads通路诱导肌成纤维细胞异常增殖,加重心肌细胞外基质沉积,使心脏组织抗纤维化能力减弱,在HF MF的发病机制中发挥复杂作用。中医药在防治HF MF方面具有明确抑制心肌胶原沉积、抗心肌纤维化、保护心肌和改善心脏功能等功效。TGF-β/Smads通路是中药单体、中药复方、中成药发挥HF心肌保护作用的关键通路之一。本文对近10年来中医药干预TGF-β/Smads通路治疗HF MF现有的实验研究成果进行综述,以期为HF MF的防治及新药开发提供理论依据。     

黄芪甲苷对心脏保护作用的研究现状

黄芪甲苷通过抑制核因子-кB(NF-кB)通路、降低NF-кB的表达水平来抑制缺氧心肌细胞的凋亡。黄芪甲苷通过调节自噬基因、上调B细胞淋巴瘤/白血病-2基因(Bcl-2),降低Bcl-2相关X蛋白(Bax)及半胱氨酸蛋白酶(caspase)-3的表达以及上调低氧诱导因子-1α(HIF-1α)表达等途径对缺血再灌注心脏发挥保护作用。黄芪甲苷也可降低心肌转化生长因子β1(TGF-β1)、Smad2/3和Smad4蛋白表达,抑制心肌纤维化,保护心脏。黄芪甲苷对异丙肾上腺素致心脏损伤、对血管紧张素Ⅱ致心脏损伤、对高血糖性心脏损伤都具有一定的保护作用。     

Regulation of endothelial nitric oxide synthase and asymmetric dimethylarginine by matrine attenuates isoproterenol-induced acute myocardial injury in rats

Objectives This study was designed to investigate the cardioprotective effects of matrine on regulation of endothelial nitric oxide synthase (eNOS) and asymmetric dimethylarginine (ADMA) in isoproterenol‐induced acute myocardial ischaemic rats. Methods Male Sprague–Dawley rats were pretreated with matrine (200, 100 and 50 mg/kg) orally for 10 days. Acute myocardial injury was induced in rats by subcutaneous injection of isoproterenol. Serum and haemodynamic parameters, histopathological variables and expression of protein levels were analysed. Key findings Oral administration of matrine (200, 100 and 50 mg/kg) significantly attenuated isoproterenol‐induced cardiac necrosis and left ventricular dysfunction. Matrine treatment restored impaired ventricular Akt and eNOS protein expression with concomitant increased phosphorylation of Akt (Ser473) and eNOS (Ser1177), and also restored glycogen synthase kinase 3β activity, as indicated by increased phosphorylation at Ser 9. Moreover, treatment with matrine had no effect on the isoproterenol‐induced elevated protein arginine methyltransferase 1 protein expression, but could significantly normalize the reduced dimethylarginine dimethylaminohydrolase 2 expression and attenuate the increased serum level of ADMA. The expression of catechol‐o‐methyltransferase and monoamine oxidase did not differ among all groups (all P > 0.05). Conclusions Our results suggested that matrine protects against isoproterenol‐induced myocardial ischaemia via eNOS and ADMA pathway.     

Targeting protein kinase B/Akt signaling with vanadium compounds for cardioprotection

Background: Akt is an important signaling molecule that modulates many cellular processes such as cell growth, survival and metabolism. Akt activation has been proposed as a potential strategy for increasing cardiomyocyte survival following ischemia. Objectives: Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia/reperfusion-induced injury along with cardiac functional recovery. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) as a potent cytoprotective agent on myocardial infarction and elicited cardiac functional recovery through activation of Akt signaling pathway. Results/conclusion: The ability of vanadium compounds to activate Akt signaling pathways are responsible for their ability to modulate cardiovascular functions and is probably beneficial as a cardioprotective drug in subjects undergoing reperfusion therapy following myocardial infarction.     

苦参碱抗心律失常的临床治疗及其机制的研究进展

苦参碱对心脏具有正性肌力和负性频率作用,在低浓度时可降低心肌自律性、高浓度时可提高其自律性.其正性肌力作用的机制系促进外钙内流,从而促进心肌细胞内的肌浆网钙大量释放所致;而负性自律性产生的机制主要与阻滞钾离子通道和钠离子通道、使动作电位时程(APD)和有效不应期(ERP)延长从而消除折返激动有关.故苦参碱可防治心力衰竭...     

苦参碱调控mTOR/p70S6K信号通路对大鼠心肌肥厚的保护作用

目的:研究苦参碱对异丙肾上腺素致大鼠心肌肥厚的保护作用及其对mTOR/p70S6K信号通路的调控。方法:大鼠皮下注射异丙肾上腺素建立慢性病理性心肌肥厚模型,将大鼠随机分为正常对照组、异丙肾上腺素(ISO)模型组、苦参碱(50,100,200 mg·kg^-1·d^-1)+ISO组和单用苦参碱(200 mg·kg^-1·d^-1)组。HE染色观察心肌病理变化;Western blot检测左心室组织中mTOR/p70S6K信号通路相关蛋白的表达。结果:与正常对照组比较,ISO模型组大鼠的心肌细胞肥大、排列紊乱,可见不同程度的纤维化、间质水肿和炎细胞浸润;苦参碱(50,100,200 mg·kg^-1·d^-1)可减轻大鼠心肌细胞肥大、纤维化、间质水肿和炎细胞浸润等ISO致心肌组织病理学结构的异常改变。与正常对照组相比,ISO模型组心肌组织内p-mTOR、p-p70S6K和p70S6K的表达显著增加;苦参碱(50,100,200 mg·kg^-1)可逆转ISO致大鼠心肌组织中p70S6K表达的上调,同时下调mTOR Ser2448和p70S6K Thr389位点的磷酸化水平,且呈剂量依赖性;mTOR表达在各组之间均无差异;单用苦参碱组与正常对照组比较无显著性差异。结论:苦参碱具有抑制ISO致大鼠心肌肥厚的作用,其机制与抑制mTOR/p70S6K信号通路有关。     

氧化苦参碱抗心律失常作用及其机制的研究进展

氧化苦参碱对心脏具有正性肌力和负性频率作用，对心肌自律性：在低浓度时降低、高浓度时提高自律性。氧化苦参碱能显著降低变为慢反应细胞的心室肌的自律性。其正性肌力作用的机制系促进外钙内流，从而促进心肌细胞内的肌浆网钙大量释放所致。而负性自律性和负性频率产生的机制与阻滞钠离子通道有关。因此氧化苦参碱能防治心力衰竭、心肌缺血和各种化学品引起的心律失常。     

和厚朴酚的心血管药理作用研究进展

和厚朴酚是二酚型疏水化合物,对糖尿病、血管紧张素II、脓毒症、烧伤、冠脉结扎缺血、缺血再灌注等引起的心肌损伤都有保护作用,能阻滞心肌肥厚和纤维化的发生发展。和厚朴酚能拮抗脂多糖或氧化型低密度脂蛋白引起的血管内皮细胞损伤,也能抑制血管平滑肌细胞增殖、迁移及血管重塑和血管新生,抑制气囊血管形成术诱导新内膜形成和血管狭窄,心血管保护作用的基本机制是抗氧化、抗炎、调血脂、降血糖和阻滞钙通道。和厚朴酚可以抑制高脂饮食引起的动脉粥样硬化形成和发展,还具有血管扩张和降压作用,因此在心血管系统疾病治疗方面有开发价值。     

Design,Synthesis, and Preliminary Cardioprotective Effect Evaluation of Danshensu Derivatives

A series of (R)‐3,4‐dihydroxyphenyllactic acid Danshensu (DSS) derivatives were synthesized, and their cardioprotective effects were evaluated in vitro and in vivo. Among the new derivatives, compound 14 showed significant protective effects in cultured myocardial cells and in the rat model of myocardial ischemia. The therapeutic efficacy of compound 14 was significantly higher than that of its parent compound DSS, and amlodipine, a first‐line treatment for angina pain. Compound 14 potently scavenged free radicals, significantly decreased the levels of LDH and MDA, and inhibited the leakage of CK in animal model of ischemia. We had previously found that compound 14 activated PI3K/Akt/GSK‐3β and Nrf2//Keap1/heme oxygenase‐1 (HO‐1) signaling pathways in H9c2 cells. These results suggest that compound 14 has a unique mechanism of action, that is, multifunctional. Compound 14 may be a new potential therapy for ischemic heart diseases.     

Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: Role of autophagy

The present study aimed to test the hypothesis that berberine, a plant‐derived anti‐oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague‐Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC‐3B, Beclin‐1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high‐dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post‐MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC‐3B II and Beclin‐1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho‐Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho‐Akt signalling pathways.     

Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart

BACKGROUND AND PURPOSE

Ischemia-reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia-reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts.

EXPERIMENTAL APPROACH

Rat isolated hearts subjected to 6 h hypothermic (1–4°C) storage followed by 45 min reperfusion at 37°C were treated with zoniporide at different concentrations and timing. Recovery of cardiac function, levels of total and phosphorylated protein kinase B, extracellular signal-regulated kinase 1/2, glycogen synthase kinase-3β and STAT3 as well as cleaved caspase 3 were measured at the end of reperfusion. Lactate dehydrogenase release into coronary effluent before and post-storage was also measured.

KEY RESULTS

Zoniporide concentration-dependently improved recovery of cardiac function after reperfusion. The functional recovery induced by zoniporide was accompanied by up-regulation of p-extracellular signal-regulated kinase 1/2 and p-STAT3, and by reduction in lactate dehydrogenase release and cleaved caspase 3. There were no significant differences in any of the above indices when zoniporide was administered before, during or after ischemia. The STAT3 inhibitor, stattic, abolished zoniporide-induced improvements in functional recovery and up-regulation of p-STAT3 after reperfusion.

CONCLUSIONS AND IMPLICATIONS

Zoniporide is a potent cardioprotective agent and activation of STAT3 plays a critical role in the cardioprotective action of zoniporide. This agent shows promise as a supplement to storage solutions to improve preservation of donor hearts.