非诺贝特对全脑缺血/再灌注损伤大鼠的保护作用

目的探讨非诺贝特对大鼠全脑缺血/再灌注损伤(I/R)的保护作用及机制。方法采用双侧颈总动脉夹闭合并低血压方法建立全脑缺血/再灌注大鼠模型。药物非诺贝特(fenofibrate,FF;33、100、300mg.kg-1)在缺血前30min灌胃给药,PPARα受体拮抗剂MK886(6mg.kg-1)在给予非诺贝特300mg.kg-1前腹腔注射。Morris水迷宫测定大鼠空间学习能力变化,病理切片HE染色观察海马神经元形态结构变化,免疫组化染色检测海马组织核转录因子NF-κBp65蛋白的表达,生化酶学方法观察超氧歧化酶(SOD)活性、丙二醛(MDA)含量变化,酶联免疫吸附法(ELISA)检测细胞因子IL-1β、IL-6、IL-10、TNF-α含量变化。结果非诺贝特能明显缩短全脑缺血/再灌注大鼠的寻台潜伏期,减轻全脑缺血/再灌注大鼠海马神经元损伤,降低海马神经元NF-κB p65蛋白表达,明显阻遏缺血/再灌注大鼠海马IL-1β、IL-6、TNF-α、MDA含量的升高和IL-10含量及SOD活性的降低;预先给予MK886能取消非诺贝特的作用。结论非诺贝特对缺血/再灌注脑损伤有明显保护作用,其机制与激活PPARα,抑制NF-κB活性,抑制CNS炎症反应和氧化应激有关。     

黄芪甲苷通过激活短链酰基辅酶A脱氢酶抑制Ang Ⅱ诱导的大鼠心肌成纤维细胞增殖和胶原表达北大核心CSCD

目的观察黄芪甲苷(astragaloside Ⅳ,AS-Ⅳ)对血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)诱导的大鼠心肌成纤维细胞(cardiac fibroblasts,CFs)增殖和胶原表达的影响。方法原代提取并体外培养大鼠CFs,用短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase,SCAD)的沉默基因SiRNA1186预处理CFs 12 h后,加入Ang Ⅱ和AS-Ⅳ共同处理36 h。Western blot检测SCAD、α-SMA、collagen Ⅰ、collagen Ⅲ的蛋白表达水平;荧光定量PCR检测SCAD、α-SMA、collagen Ⅰ、collagen Ⅲ的mRNA表达水平;检测各组CFs中SCAD酶活性、ATP、羟脯氨酸和游离脂肪酸含量变化。结果Ang Ⅱ作用CFs 36 h后,与空白对照组比较,Ang Ⅱ组CFs增殖率,α-SMA、Collagen Ⅰ、Collagen Ⅲ的蛋白和mRNA表达水平明显增加(P均<0.01),SCAD表达和酶活性均明显降低(P<0.01,P<0.05),ATP生成减少(P<0.01),羟脯氨酸和游离脂肪酸含量升高(P均<0.01);AS-Ⅳ给药处理后,CFs增殖和胶原表达明显减少(P均<0.01),SCAD表达和酶活性明显升高(P均<0.01),ATP生成增加(P<0.01),羟脯氨酸和游离脂肪酸含量减少(P均<0.01);然而,与Ang Ⅱ+NC组相比,Ang Ⅱ+SiRNA1186+AS-Ⅳ组各项指标均无差异,在SCAD SiRNA1186的干扰下,AS-Ⅳ对Ang Ⅱ诱导的CFs增殖和胶原表达的保护作用被取消。结论AS-Ⅳ可能通过激活SCAD,从而抑制Ang Ⅱ诱导的大鼠心肌成纤维细胞增殖和胶原表达。     

小檗碱对脂质代谢相关基因PPARα和CPTIA表达的影响

目的研究小檗碱(Berberine,Ber)对HepG2细胞的PPARα基因及其调控基因CPTⅠA表达的影响。方法以PPARα激动剂非诺贝特作阳性对照药,采用RT-PCR法研究Ber对HepG2细胞PPARα基因及其调节基因CPTⅠAmR-NA表达影响的时—效和量—效关系。结果非诺贝特明显促进CPTⅠAmRNA表达;Ber也呈浓度和时间依赖性促进CPTⅠAmRNA的表达,而对PPARαmRNA表达无影响;PPARα特异拮抗剂MK-886能阻断非诺贝特和Ber上述作用。结论Ber可能通过激动PPARα促进与脂质代谢相关的靶基因CPTⅠAmRNA的表达。     

PPARα、PPARγ的上调参与淫羊藿苷对自发性高血压大鼠心室重构的调节

目的观察淫羊藿苷(icariin,Ica)对自发性高血压大鼠(SHR)心室重构的作用,并探讨其机制。方法 14周龄♂SHR大鼠21只随机分为模型组,Ica低、高剂量组(20、40mg·kg-1,ig,bid),14周龄♂WKY大鼠为空白对照组,空白对照组和模型组给予等体积的双蒸水灌胃。适应性喂养1周,连续灌胃12周后处死全部动物,采用双抗体夹心法测定左心羟脯氨酸的含量;Masson染色观察左心室组织病理学变化;real-time RT-PCR、Western blot分别检测PPARα、PPARγm RNA和蛋白的表达。结果与空白对照组相比,模型组出现心室重构,心肌纤维化,心肌组织羟脯氨酸含量明显上升(P<0.01),PPARα、PPARγm RNA和蛋白表达明显降低(P<0.05或P<0.01)。与模型组相比,Ica低、高剂量组心肌细胞排列较整齐,心肌纤维化减少,且心肌羟脯氨酸含量降低,PPARα、PPARγm RNA和蛋白表达升高(P<0.05或P<0.01)。结论淫羊藿苷具有减轻自发性高血压大鼠心室重构的作用,其机制可能与上调PPARα、PPARγ有关。     

阿托伐他汀对自发性高血压大鼠MAI及ET-1蛋白、eNOS蛋白、TNF-α蛋白表达的影响

目的:观察阿托伐他汀对自发性高血压(SHR)大鼠MAI及TNF-α蛋白、ET-1蛋白、eNOS蛋白表达的影响。方法:20只雄性SHR随机分为阿托伐他汀干预组(ATV组)和生理盐水组(NS组),10只正常血压雄性大鼠给予生理盐水灌胃作对照(WKY组)。观察10周后心肌组织和血清中TNF-α、ET-1、eNOS的表达,检测MAI变化。结果:NS组大鼠和ATV组大鼠与WKY组大鼠相比,左室MAI、血清及左室心肌中TNF-α蛋白和血清中ET-1蛋白表达明显升高(P<0.05),而ATV组大鼠与NS组大鼠比较,上述指标均显著低于NS组(P<0.05);eNOS活性显著降低(P<0.05),而ATV组大鼠与NS组大鼠比较,上述指标均显著低于NS组(P<0.05);eNOS活性则显著升高(P<0.05)。结论:阿托伐他汀抑制高血压大鼠心肌细胞凋亡,可能与其抑制TNF-α、ET-1蛋白的表达,提高eNOS活性有关。     

苯那普利及坎地沙坦对自发性高血压大鼠心肌肥厚过程中SMAD蛋白的影响

目的观察自发性高血压大鼠(SHR)心肌肥厚程度与转化生长因子β1(TGF-β1)、Smad3和Smad7蛋白的表达及苯那普利、坎地沙坦的治疗作用。方法12wk龄SHR连续灌胃给予苯那普利或(和)坎地沙坦,每2wk测定尾动脉压,12wk后检测心脏构型、心脏指数、心肌细胞大小、心肌和血浆AngⅡ含量、心肌中TGF-β1、Smad3和Smad7蛋白的表达。结果SHR血压、心脏指数、心肌细胞大小及心肌组织中TGF-β1、Smad3蛋白明显增加,苯那普利或坎地沙坦治疗均能使上述指标减轻,联合应用具有协同作用,且能降低心肌和血浆AngⅡ含量;苯那普利或坎地沙坦治疗能增加在SHR中表达下降的Smad7蛋白,但两者合用对Smad7表达改善不明显。结论苯那普利和坎地沙坦联合应用对改善自发性高血压大鼠心肌肥厚具有协同作用,可能与调节AngⅡ水平、减少高血压心肌肥厚过程中TGF-β1和Smad3表达有关。     

缬沙坦对自发性高血压大鼠心肌抑癌基因PTEN表达的影响

目的 :观察缬沙坦对自发性高血压大鼠(SHR)心肌肥厚的影响 ,以及对肿瘤抑制基因PTEN表达的影响。方法 :取 2 0只 12周龄自发性高血压大鼠 ,随机分为 2组 ,每组 10只 :缬沙坦干预组 ,给予缬沙坦 30mg·kg-1·d-1溶于饮水灌胃治疗 ;SHR阳性对照组给予正常饮水。另有 10只同龄同源雄性正常血压Wistar kyoto大鼠 (WKY组 )作为正常对照组。实验周期 8周 ,测量血压、左室重量 体重(LVW BW ) ,应用免疫组化方法检测各组大鼠左心室心肌PTEN的表达。结果 :SHR阳性对照组血压、LVW BW均高于正常对照组 ,但低于缬沙坦组 ,SHR阳性对照组PTEN的表达明显低于正常对照组 ,而缬沙坦组PTEN的表达显著高于SHR阳性对照组。结论 :缬沙坦能抑制自发性高血压大鼠心肌肥厚 ,并能提高PTEN的表达 ,提示PTEN可能在心肌肥厚发展过程中起了一定的作用。     

非诺贝特抑制血管紧张素Ⅱ所诱导的心脏成纤维细胞骨桥蛋白表达升高

目的：探讨过氧化物酶体增殖物激活受体α（PPARα）激动剂非诺贝特对血管紧张素Ⅱ（An-gⅡ）诱导的心脏成纤维细胞骨桥蛋白表达升高的影响。方法：分离并传代培养SD大鼠乳鼠心脏成纤维细胞,使用不同浓度（0、25、50、100μmol/L）的非诺贝特预处理1h后,加入An-gⅡ作用24h。分别采用实时定量PCR法和Western blotting技术检测骨桥蛋白mRNA和蛋白表达情况。结果：非诺贝特显著抑制AngII诱导的心脏成纤维细胞骨桥蛋白mRNA及蛋白的表达,并且呈剂量依赖性。结论：非诺贝特对心脏成纤维细胞中骨桥蛋白的表达具有明显的抑制作用,这可能是其在心血管系统发挥抗纤维化和抗炎作用的部分机制。     

非诺贝特对高脂血症兔血清及脂肪细胞分泌肿瘤坏死因子-α的影响

目的　观察非诺贝特干预对高脂血症兔血清及脂肪细胞分泌肿瘤坏死因子 α(TNF α)的影响,并探讨其可能机制。方法　10只新西兰大白兔给予高胆固醇饮食饲养 8w后,随机分为两组:①高胆固醇组:继续饲以高胆固醇饲料wk;②非诺贝特组:在饲以高胆固醇饲料的基础上给予非诺贝特(30mg·kg-1·d-1 ),共 4wk。另选普通饮食 12wk兔(n=5)作为对照组。取腹股沟皮下脂肪组织称量,并行脂肪细胞培养,酶联免疫吸附法 (ELISA)检测血清及脂肪细胞培养液中TNF α水平。半定量逆转录多聚酶链式反应 (RT PCR)测定脂肪细胞PPARαmRNA的表达。结果　高胆固醇组血清总胆固醇、低密度脂蛋白胆固醇水平明显高于对照组(P<0 01),非诺贝特干预 4wk未对血脂产生明显影响,但能降低体重 ( -19% )及皮下脂肪量 ( -40% ),并能降低血清TNF α水平 ( -44 7%,与高胆固醇组比,P<0 05 )。非诺贝特呈剂量依赖性降低脂肪细胞分泌TNF α。三组兔脂肪细胞PPARαmRNA表达差异无显著性。结论　非诺贝特能独立于降脂作用外降低高胆固醇饮食饲养兔体重和皮下脂肪量并降低血清及脂肪细胞分泌TNF α,这一作用可能有利于动脉粥样硬化及肥胖的防治。     

PPAR—α信号通路参与高糖高胰岛素诱导的心肌细胞肥大

目的：研究过氧化物酶体增值物激活受体-α（Peroxisome proliferator-activated receptor,PPAR-α）信号转导通路在高糖高胰岛素诱导心肌细胞肥大中的作用。方法：利用乳鼠心肌细胞培养,以细胞表面积、蛋白含量和心房利钠因子（atrial natriuretic factor,ANF）mRNA表达为心肌肥大反应指标,观察PPAR-α激动剂非诺贝特及其相应阻断剂MK886对高糖高胰岛素致心肌肥大作用的影响。利用Realtime—PCR方法和westemblot方法分别检测PPAR—α及其下游因子环氧化酶-2（Cyclooxygenase2,Cox-2）mRNA及蛋白的表达。结果：在高糖高胰岛素模型组（25．5mmol／L葡萄糖与0．1gmol／L胰岛素）,心肌细胞表面积、总蛋白含量和ANFmRNA表达明显增加（P〈0．01）;但PPAR-αmRNA和蛋白的表达明显降低（P〈0．05）;同时,Cox-2mRNA和蛋白的表达增加,明显高于对照组（P〈0．05）。然而PPAR-α的选择性激动剂非诺贝特（10^-6、3&#215;10^-6和10^-5mol／L）呈浓度依赖性地抑制高糖高胰岛素诱导的心肌细胞肥大（P〈0．01）。非诺贝特3&#215;10^-6mol／L明显上调高糖高胰岛素模型组PPAR-αmRNA和蛋白的表达（P〈0．05）,并阻遏其下游损伤性炎性因子Cox-2mRNA和蛋白的表达（P〈0．05）。同时,MK886可完全阻断非诺贝特对高糖高胰岛素诱导心肌细胞肥大模型组的上述改善作用（P〈0．05）。结论：PPAR-α及其下游炎症因子Cox-2参与了高糖高胰岛素诱导的心肌细胞肥大。     

丹参酮ⅡA对自发性高血压大鼠左心室谷胱甘肽-s-转移酶μ2表达的影响

目的：观察丹参酮ⅡA对自发性高血压大鼠（SHR）左心室谷胱甘肽-s-转移酶μ2（glutathione-s-transferase μ2,GSTμ2）表达的影响,探讨丹参酮ⅡA防治左心室肥厚的机制。方法：实验分3组：（1）正常对照组;（2）SHR组;（3）丹参酮ⅡA组。处理后检测血流动力学指标、左室重量指数及大鼠左心室GSTμ2的活性,采用共聚焦显微镜检测左心室O2^.-的产生情况,Western blotting检测GSTμ2的表达情况。结果：SHR组血压与左室重量指数均显著高于正常对照组,左心功能明显下降;丹参酮ⅡA显著逆转了SHR的左心室肥厚,但未明显改善高血压。SHR组左心室O2^.-的产生较正常对照组显著增多,而丹参酮ⅡA治疗后,O2^.-产生较SHR组显著减少。GSTμ2的表达及活性在SHR组显著降低,而丹参酮ⅡA显著增加了GSTM2的表达及活性。结论：丹参酮ⅡA能逆转SHR的左心室肥厚,这可能与其增加GSTμ2表达,减少活性氧产生,消除氧化应激有关。     

Enhanced susceptibility to histamine-induced cardiac arrhythmias in spontaneously hypertensive rats.

To clarify mechanisms underlying an enhanced susceptibility to cardiac rhythm disturbances in hypertension and myocardial hypertrophy, we evaluated the vulnerability to histamine-induced arrhythmias of isolated left ventricles from spontaneously hypertensive rats (SHR) and age-matched controls (Wistar-Kyoto rats, WKY). Before drug administration, left ventricle-to-body weight ratios, spontaneous firing rates, and the incidence of arrhythmias (including delayed afterdepolarizations) were significantly increased in SHR ventricles versus WKY. In addition, action potential duration (APD) was prolonged in SHR at all levels of repolarization. In WKY but not SHR hearts, histamine (10(-7)-10(-4) M) increased spontaneous firing rates; the incidence of arrhythmias was increased in all hearts, but the response to histamine was most pronounced and occurred at lower threshold drug levels in SHR. After potentials and triggered activity were observed only in SHR. The H2-receptor blocker cimetidine (10(-5) M) and the Ca2(+)-channel antagonist verapamil (10(-6) M) each attenuated the arrhythmogenic influence of histamine in SHR and WKY preparations. Neither chlorpheniramine nor propranolol had any effect. The enhanced vulnerability to arrhythmogenesis observed in SHR myocardium may reflect elevated intracellular calcium levels, which may in turn be potentiated by local ischemia and/or intracardiac histamine release.     

The effects of quinapril and atorvastatin on artery structure and function in adult spontaneously hypertensive rats

We studied the combined treatment effects of quinapril and atorvastatin on blood pressure and structure and function of resistance arteries from adult spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY rats). Apoptotic cells were identified by in situ end labeling using the terminal deoxynucleotide transferase-mediated dUTP nick end labeling method. Vascular structure was measured using a morphometric protocol and confocal microscopy and a pressurized artery system was used to study vascular functions. We found that a combined treatment with quinapril and atorvastatin lowered systolic blood pressure in both adult SHR and WKY rats and decreased medial thickness and volume and the number of smooth muscle cell layers in mesenteric arteries, as well as media-to-lumen ratio in the interlobular arteries from SHR but not in those from WKY rats. The number of apoptotic smooth muscle cells was higher in the mesenteric arteries from control WKY rats than control SHR and treatment increased the number of apoptotic smooth muscle cells in the arteries from both SHR and WKY rats. Treatment with quinapril and atorvastatin reduced ventricular weight in SHR and normalized the augmented contractile responses to norepinephrine but did not alter the contraction to electric field stimulation. Relaxation responses to acetylcholine and sodium nitroprusside were not affected by the treatment. We conclude that a combined treatment with quinapril and atorvastatin lowered blood pressure and improved cardiac and vessel hypertrophy and vessel function. An increase in apoptotic smooth muscle cells may be one of the mechanisms underlying the structural improvement.     

高血压性左心室肥厚与心肌原癌基因c-fos表达

采用自发性高血压大鼠(SHR)和两肾一夹型(2K1C)肾血管性高血压大鼠模型，研究细胞核内原癌基因c-fos在高血压性左心室肥厚(LVH)发生，发展过程中的作用. 结果表明：SHR在8-10周龄时已有明显的高血压和LVH，其收缩压(SBP)与左室重/体重比(LVW/BW)均显著高于同龄的WKY大鼠. 20-22周龄与40-42周龄时，SHR的SBP，LVW/BW及左心室c-fos基因表达水平均明显高于同龄对照组WKY大鼠. 2K1C大鼠左肾动脉缩窄1周后发生明显的LVH，同时伴左心室c fos基因的高表达，至术后3和10周仍保持较高水平. 钙拮抗剂尼群地平(10 mg·kg^-1 ig，每日2次，连续10周)或血管紧张素AT₁受体阻断剂洛沙坦(30 mg·kg^-1·d^-1 ig，连续10周)治疗均可逆转2K1C大鼠SBP的增高和LVH的发生与发展，同时左心室c-fos基因表达水平降低. 结果提示心肌原癌基因c-fos的高表达参与高血压性LVH的发生，发展过程.     

Regulation of phospholamban and sarcoplasmic reticulum ca<Superscript>2+</Superscript>-atpase by atorvastatin: implication for cardiac hypertrophy

Abnormal intracellular Ca2+ homeostasis in the myocardium has been suggested as the cause of cardiac hypertrophy, and this process can be prevented by the HMG-CoA reductase inhibitors, statins. In the present study, the effect of atorvastatin on left ventricular hypertrophy was investigated, and then whether the underlying mechanism was related to a defect in intracellular Ca2+ homeostasis explored. Twelve spontaneously hypertensive rats (SHR), at 8 weeks old, were used in this study, and received either distilled water or atorvastatin for ten weeks, with age-matched normotensive Wistar-Kyoto rats (WKY) used as controls. RT-PCR and western blotting were used to detect the mRNA and protein expressions of phospholamban (PLB) and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), respectively, and a colorimetric method used to examine the SERCA2a activity. Additionally, cardiac hypertrophic indices, such as the cardiosomatic ratio, left ventricular weight to body weight (LVW/BW) ratio and cardiomyocytes transverse diameter (TDM), together with the systolic blood pressure (SBP) and serum lipids levels were also examined. After ten weeks, significant decreases were observed in both the mRNA and protein expression levels of SERCA2a, as well as its activity, in the hypertrophied hearts of the SHR. The administration of atorvastatin to the same strains of rats effectively inhibited these decreases, and the above cardiac hypertrophic indices, as well as the SBP and serum lipids levels were significantly decreased. However, no significant changes in the expressions of PLB were observed in WKY, SHR and atorvastatin-treated SHR. These findings demonstrated that through regulation of the PLB and SERCA2a levels in the hearts of SHR, atorvastatin can prevent the cardiac hypertrophy caused due to pressure overload, which provides a relatively new insight into the mechanism of atorvastatin in the prevention of cardiac hypertrophy.     

缬沙坦降低慢性肾衰竭大鼠心肌内皮素的表达

目的：观察缬沙坦对慢性肾衰竭大鼠心肌肥厚及心肌内皮素-1（ET-1）表达的影响,探讨其作用机制。方法：SD雄性大鼠24只,通过5/6肾切除法制备慢性肾衰竭模型,术后2周随机分为模型组、缬沙坦组,并设假手术组作为对照。术后第10周末测定各组大鼠血压及肾功能（BUN、Cr）后处死大鼠,取出心脏进行病理组织形态学观察;并采用原位杂交方法检测心肌ET-1 mRNA转录水平。结果：模型组术后第10周收缩压、心脏重量、心脏重量指数、左室重量及左室重量指数均明显增加,缬沙坦组能显著降低5/6肾切除大鼠收缩压、心脏重量、心脏重量指数、左室重量及左室重量指数（P〈0.01）;缬沙坦组心肌ET-1 mRNA转录水平较模型组减弱。结论：缬沙坦能改善慢性肾衰竭大鼠的左室肥厚,其机制可能是通过下调心肌ET-1 mRNA转录来实现的。     

Histamine attenuates the arrhythmogenic effects of norepinephrine in hearts of spontaneously hypertensive rats

A potential physiological role for cardiac histamine and its interaction with norepinephrine were investigated in isolated left ventricles from spontaneously hypertensive rats (SHR). Prior to drug administration, left ventricle-to-body weight ratios and spontaneous firing rates (beats per min) were significantly increased in SHR ventricles vs. age- and sex-matched controls (WKY). Also, action potential duration was significantly prolonged in SHR at all levels of repolarization. In all hearts, norepinephrine (10(-7)-10(-4) M) increased spontaneous rate and the percent incidence of arrhythmias. The H2-receptor antagonist cimetidine (10(-5) M) potentiated the rate and arrhythmogenic effects of norepinephrine in SHR and, to a lesser extent, in WKY preparations; propranolol (10(-6) M) reduced them. Histamine (10(-7) M) also inhibited the norepinephrine-induced increase in arrhythmias in SHR, but not in WKY. The attenuation of adrenergically induced rhythm disturbances by histamine and their potentiation by cimetidine in hypertensive hearts support the hypothesis that histamine plays a role as a postjunctional modulator of adrenoceptor function in a setting of hypertension and myocardial hypertrophy.     

ANGIOTENSIN CONVERTING ENZYME INHIBITOR, CAPTOPRIL, INHIBITS CARDIAC HYPERTROPHY WITHOUT CHANGING COLLAGEN TYPES AND CONCENTRATION IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The effects of the ACE inhibitor, captopril, on collagen metabolism in spontaneously hypertensive rats (SHR) with cardiac hypertrophy was examined. Captopril (100 mg/kg per day) was administered in drinking water to 20 week old male SHR for 12 weeks. Collagen concentration was calculated from hydroxyproline content, and relative proportions of types I, III and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). These parameters were examined in age and sex matched Wistar-Kyoto (WKY) rats, as well as in non-treated SHR, and compared with those of captopril-treated SHR. 2. Captopril significantly reduced both blood pressure (191 ± 12.1 vs 146 ± 11.2 mmHg, P < 0.01), and the ratio of left ventricular (LV) weight to bodyweight (BW; 2.38 ± 0.17 vs 2.05 ± 0.12 mg/g, P < 0.01). There were no significant differences in collagen concentration among WKY rats, captopril-treated SHR and non-treated 32 week old SHR. However, total collagen content in captopril-treated SHR reduced significantly compared with non-treated 32 week old SHR (16.8 ± 2.0 vs 21.3 ± 0.8 mg, P < 0.01). The relative proportion of type V collagen was significantly higher in both captopril-treated (58.6 ± 3.4 vs 46.8 ± 1.3%, P < 0.01) and non-treated 32 week old SHR (59.9 ± 3.1 vs 46.8 ± 1.3%, P < 0.01) compared with WKY rats. However, there were no significant differences between captopril-treated SHR and non-treated 32 week old SHR. 3. The data from this study showed that captopril reduced cardiac hypertrophy, as reported previously, but did not change collagen types and concentration of the hypertrophied myocardium in SHR.     

Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats

Farnesyl pyrophosphate synthase (FPPS), an essential enzyme in the mevalonate pathway, was reported to be upregulated in young spontaneously hypertensive rats (SHR) when compared with Wistar-Kyoto (WKY) rats, and this was accompanied by development of left ventricular hypertrophy. Five-week-old rats were daily gavaged with vehicle or an FPPS inhibitor (alendronate, 1 or 10 mg/kg) and blood pressures was monitored by the tail-cuff method every other week. Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio (LVW/BW), hydroxyproline content, collagen deposition in the interstitia, and gene expression of atrial natriuretic peptide, B-type natriuretic peptide, and procollagen type I/III in the SHR left ventricle, all of which were significantly higher in SHRs than in WKY rats. Furthermore, long-term treatment with an FPPS inhibitor significantly reduced RhoA activation, ERK phosphorylation, and TGF-β1 expression in the SHR left ventricle, all of which were upregulated more in SHRs than in WKY rats. In conclusion, chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis, and the suppression of ERK1/2 phosphorylation and TGF-β1 expression with inhibition of RhoA activation may be an important mechanism.     

依那普利对肾性与自发性高血压大鼠左心室Eno1及GSTM2表达的影响

目的观察依那普利对肾性与自发性高血压大鼠左心室α-烯醇化酶(α-enolase,Eno1)及谷胱甘肽-s-转移酶,μ2(glutathione-s-transferase,μ2,GSTM2)表达的影响。方法实验共分5组:(1)对照组;(2)两肾两夹高血压大鼠组;(3)两肾两夹高血压大鼠+依那普利组;(4)自发性高血压大鼠组;(5)自发性高血压大鼠+依那普利组。检测各组大鼠血压及左室重量指数,行超声心动图检查,并运用Western blot检测各组大鼠左心室Eno1、GSTM2及β-肌球蛋白重链(β-myosin heavy chain,β-MHC)的表达情况。结果两肾两夹及自发性高血压大鼠血压与左室重量指数均明显高于对照组,依那普利治疗后,其左心室肥厚均得到明显逆转。与两肾两夹组相比,Eno1在自发性高血压大鼠中的表达明显上调;与对照组相比,GSTM2在自发性高血压大鼠中的表达明显下调,而两肾两夹组无变化,经依那普利治疗后,二者的表达变化均未得到明显逆转;β-MHC在两种模型中的表达均上调,而依那普利治疗后,β-MHC在二者中的表达均明显下调。结论依那普利能明显逆转β-MHC在两种模型中的差异表达,但不能逆转Eno1和GSTM2在二者中的差异表达。