花生四烯酸介导炎症相关心肌纤维化研究进展

心脏左室纤维化进展作为心脏功能不利因素目前逐渐受到心脏科医生关注。大量研究证据表明,炎症细胞的浸润是心肌纤维化进程中的关键步骤。炎症细胞可以释放花生四烯酸并使其在环氧化酶、脂氧化酶或细胞色素P450表氧化酶等催化物作用下生成具有生物活性的产物,如前列腺素、白三烯、环氧花生四烯酸以及羟基花生四烯酸。这些产物中部分具有促纤维化作用,并参与炎症细胞介导的心肌纤维化通路。现将对目前心肌纤维化通路研究做一综述。     

缬沙坦治疗对自发性高血压大鼠心肌纤维化的影响

目的　观察缬沙坦对自发性高血压大鼠 (SHR)心肌纤维化的影响。方法　 3 0只 12周龄雄性SHR大鼠 ,随机分成3组 :(1)大剂量缬沙坦组 (n =10缬沙坦 3 0mg/kg·d) ;(2 )小剂量缬沙坦组 (n =10缬沙坦 10mg/kg·d) ;(3 )SHR空白对照组 (n =10 ) ;(4)同龄雄性正常血压WKY大鼠对照组 (n =10 )。给药 4周 ;天狼星红染色法使胶原特殊染色 ,计算机图象分析测量心肌切片的胶原容积分数和心肌小动脉周围胶原面积与小动脉面积比表示心肌纤维化程度。结果　与SHR组相比大小剂量缬沙坦组 ,均能有效降低SHR血压 (P <0 0 5)。并能改善SHR大鼠左心室肥厚 (P <0 0 5)并使心室内、外膜及心肌小动脉周围的胶原减少 ,其中大剂量组各指标均较SHR有显著差异 (P <0 0 5)。结论　缬沙坦对SHR大鼠的心肌纤维有显著的抑制作用     

缬沙坦治疗对自发性高血压大鼠心肌纤维化的影响

目的观察缬沙坦对自发性高血压大鼠(SHR)心肌纤维化的影响.方法 30只12周龄雄性SHR大鼠,随机分成3组(1)大剂量缬沙坦组(n=10 缬沙坦30 mg/kg*d);(2)小剂量缬沙坦组(n=10 缬沙坦10 mg/kg*d); (3)SHR空白对照组(n=10);(4) 同龄雄性正常血压WKY 大鼠对照组(n=10).给药4周; 天狼星红染色法使胶原特殊染色,计算机图象分析测量心肌切片的胶原容积分数和心肌小动脉周围胶原面积与小动脉面积比表示心肌纤维化程度.结果与SHR组相比大小剂量缬沙坦组,均能有效降低SHR血压(P<0.05).并能改善SHR大鼠左心室肥厚(P<0.05)并使心室内、外膜及心肌小动脉周围的胶原减少,其中大剂量组各指标均较SHR有显著差异(P<0.05).结论缬沙坦对SHR大鼠的心肌纤维有显著的抑制作用.     

自发性高血压大鼠心肌超声显像灰度的改变与左室病理变化的对比观察

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老年自发性高血压大鼠动态血压的测定及特征研究

目的 比较植入式生理信号遥感技术和尾套法监测自发性老年高血压大鼠(SHR)血压差异,并观察其血压特征.方法 40周龄及16周龄SHR各5只,使用尾套法和植入式生理信号遥感技术测量清醒、无拘束SHR的动态血压变化,对血压昼夜变化及变异度进行分析.结果 尾套法测得SHR的收缩压[16周龄为(191.3±2.5)mm Hg,40周龄为(190.9±2.8)mm Hg],高于植入式生理信号遥感技术测得收缩压[16周龄为(165.1±8.8)mm Hg,40周龄为(170.4±17.1)mm Hg],且遥测法能获得准确的舒张压数值[16周龄为(120.1±8.5)mm Hg,40周龄为(122.6±14.4)mm Hg],而尾套法不能.植入式生理信号遥感监测技术测得40周龄SHR脉压均值较16周龄高[分别为(48.8±9.6)mm Hg和(44.9±6.4)mm Hg,P＜0.05)];其他指标二者比较,差异无统计学意义(均为P＞0.05).40周龄SHR较16周龄24 h血压均值升高,但差异无统计学意义(P＞0.05).40周龄SHR血压变异系数较16周龄明显增加(P＜0.05).结论 老年清醒、无拘束SHR的24 h血压变异较16周龄成年鼠明显增加,血压昼夜调节能力下降.     

血脂康胶囊对自发性高血压大鼠心肌肥厚的早期干预研究

目的研究血脂康胶囊对幼年自发性高血压大鼠（spontaneous hypertensive rat, SHR）心肌肥厚的影响。方法24只6周龄雄性SHR分为低剂量血脂康胶囊组（A组,n=8）、高剂量血脂康胶囊组（B组,n=8）和安慰剂组（C组,n=8）,另设WKY（Wistar—kyoto rats）组（W组,n=8）。A组和B组分别以血脂康胶囊20mg·kg^-1·d^-1和200mg·kg^-1·d^-1 0．9％氯化钠溶液溶解后灌胃;C组和W组以等容积0．9％氯化钠溶液灌胃,连续8周。腹主动脉采血,用酶联免疫吸附测定方法测定血浆一氧化氮（NO）和氧化低密度脂蛋白（oxidized low-density lipoprotein, ox-LDL）浓度;超声心动图测定室间隔舒张期厚度（interventricular septal thickness, IVSd）和左心室后壁舒张期厚度（left ventricular posterior wall thickness, LVPWd）;取心肌标本,称取左心室质量,计算左心室质量指数（left ventricular mass index, LVMI）,制备心肌组织石蜡切片,苏木精一伊红染色,观察心肌细胞直径和心肌细胞面积。结果与W组比较,C组血浆一氧化氮浓度降低,ox-LDL浓度升高,LVMI、IVSd、LYPWd、心肌细胞直径和心肌细胞面积均增加,差异有统计学意义（P〈0．05）;与C组比较,B组上述指标明显改善,差异有统计学意义（P〈0．05）;而A组仅血浆一氧化氮和ox—LDL浓度改善。结论自发性高血压大鼠发生心肌肥厚,血脂康胶囊早期干预可改善SHR心肌肥厚。     

丹参对自发性高血压大鼠心肌醛固酮合成的抑制作用及其机制

目的　研究丹参对自发性高血压大鼠 (SHRs)心肌醛固酮合成的作用及可能机制。方法　 12周龄雄性SHRs 30只和WKY大鼠 15只 ,分为 3组 :对照组、高血压组、丹参组。丹参组经腹腔给予丹参注射液 1 5mg/ (kg·d)共 12周。采用放射免疫法、荧光分光光度法和逆转录聚合酶链反应 (RT PCR)技术测定各组心肌组织醛固酮含量、醛固酮合成酶活性及醛固酮合成酶基因CYP11B2的mRNA表达水平。结果经丹参治疗后SHRs心肌醛固酮含量及醛固酮合成酶活性明显降低 (P <0 0 1,P <0 0 5 ) ,分别下降 5 1 3%、39 7% ,CYP11B2基因的mRNA表达水平显著下调(P <0 0 1)。结论丹参可能通过下调醛固酮合成酶基因CYP11B2的表达 ,降低醛固酮合成酶的活性 ,从而抑制心肌醛固酮的合成     

环氧化酶-2与肝癌

环氧化酶（Cyclooxygenase,COX）是合成前列腺素（prostaglandins,PG）过程中一个重要的限速酶,可催化花生四烯酸转化为各种前列腺素产物,从而维持机体的各种生理病理过程。COX是一种膜结合蛋白,哺乳动物中的COX至少有两种类型：COX-1和COX-2。COX-1是结构型酶,参与维持机体正常的生理功能。COX-2是诱导型酶,正常生理状态下在多数组织内检测不到,当细胞受到炎症刺激后便开始合成表达。COX-2除了在炎症反应中起重要作用外,还与多种消化系统肿瘤的关系密切,尤其是肝癌。     

软脉灵对自发性高血压大鼠心肌纤维化的作用

目的 观察软脉灵对自发性高血压大鼠(SHR)心肌纤维化的影响.方法 选择12周龄雄性SHR 36只,随机分为4组,软脉灵大剂量和小剂量组、空白组、阳性对照组.血压正常的京都Wistar大鼠(WKY)为正常对照组(WKY组).治疗前及治疗12周后用尾袖法测定动脉血压,称重后处死,取心脏,计算左心室重量与体重比(LVM/BW),天狼星红染色,计算心肌胶原容积分数.结果 软脉灵大剂量、小剂量组治疗12周后,收缩压(SBP)均显著低于空白组(P<0.01).与空白组相比,软脉灵大剂量组对SHR心肌外斜层纤维化有明显抑制作用(P<0.01),而软脉灵小剂量组则无影响;与空白组相比,软脉灵大剂量和小剂量组对SHR心肌中环层纤维化及心肌血管周围纤维化均有明显抑制作用(P<0.01).结论 软脉灵可以抑制SHR血压的发展,抑制SHR的心肌纤维化.     

通心络治疗对自发性高血压大鼠心肌纤维化的影响

目的：观察通心络对自发性高血压大鼠(SHR)心肌纤维化的影响。方法：30只12周龄雄性SHR大鼠，随机分成大剂量通心络组、小剂量通心络组、SHR空白对照组3组，每组10只；另取10只同龄雄性正常血压WKY大鼠作为对照组。给药12周，天狼星红染色法使肢原特殊染色，计算机图像分析测量心肌切片的肢原容积分数和心肌小动脉周围肢原面积与小动脉面积比表示心肌纤维化程度；放免法(RIA)测定血浆AngⅡ的浓度：结果：与SHR组相比，大、小剂量通心络组均能在一定程度上抑制S服血压升高(P＜0．05)。通心络大、小剂量组治疗均能在一定程度上改善SHR大鼠左心室肥厚(P＜0．05)，并使心室内、外膜及心肌小动脉周围的胶原减少，同时血浆AngⅡ浓度较SHR组下降，其中大剂量组各指标均较SHR有统计学意义(P＜0．05)。结论：通心络对SHR大鼠的心肌纤维化有显著的抑制作用。     

Trimethylamine-N-oxide (TMAO) increased aquaporin-2 expression in spontaneously hypertensive rats

Recent evidence suggests that elevated plasma levels of Trimethylamine-N-oxide (TMAO) can prolong the duration of elevated blood pressure in rats. The purpose of this study was to investigate the plasma TMAO level in Spontaneously Hypertensive Rats (SHR) and to explore the possible relationship between TMAO and aquaporin-2 (AQP-2) in the formation of hypertension. Twelve-week-old, male Spontaneously Hypertensive rats (SHR, n = 40) and Wistar-Kyoto rats (WKY, n = 40) were accordingly grouped into SHR group and WKY group. Each group was divided randomly into four subgroups: Untreated group, TMAO group, TMAO+Tolvaptan (TMAO+TVP) group, and TVP group, respectively. Systolic blood pressure (SBP), plasma TMAO, plasma osmolality (POsm), plasma vasopressin (PAVP), and plasma AQP-2 (PAQP-2) concentration were measured, and the expression of AQP-2 in kidney medulla was detected by RT-PCR and Western blot. At 14 weeks, rats in SHR TMAO group were shown the increased plasma TMAO, POsm, PAVP, and PAQP-2 levels, while those rats in SHR TMAO+TVP group were shown the decreased plasma TMAO, POsm, and PAQP-2 levels, but an even higher PAVP (due to the blockage of TVP to V2 receptor). These findings indicate that an increase of plasma TMAO levels in SHR leads to a higher plasma osmotic pressure, triggers the regulation of the TMAO-AVP-AQP-2 axis in SHR, elicits the greater water reabsorption, and eventually leads to hypertension.     

丹参预防自发性高血压大鼠左心室肥厚

目的　观察丹参对自发性高血压大鼠左室肥厚的作用。方法　 18只 8周龄的自发性高血压大鼠随机分成 3组 :一组于 8周处死 ,另两组分别经腹腔注射丹参和蒸馏水 (1g/kg·d) ,共 10周。测量大鼠尾动脉收缩压 (SBP)及左心室重量指数 (LVMI)。应用HE、VG染色 ,结合计算机图像分析技术 ,检测心肌细胞的直径 (TDM)、面积 (CA)、心肌组织胶原体积比例 (CVF)、血管周围胶原面积和管腔面积比例 (PVCA)。结果　与 8周龄的自发性高血压大鼠相比 ,18周龄大鼠的SBP、LVMI、心肌细胞的直径、面积、CVF、PVCA显著增加 (P <0 0 1) ,丹参治疗组大鼠反映左室肥厚的各项指标上升不明显 (P >0 0 5 ) ,但收缩压仍显著升高 (P <0 0 1)。结论　长期应用丹参治疗可预防自发性高血压大鼠左室肥厚的形成。     

Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats

Endothelial cells represent an important vascular site of signaling and development of damage during ischemia, inflammation and other pathological conditions. Excessive reactive oxygen species production causes pathological activation of endothelium including exposure of cell to adhesion molecules. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members of the immunoglobulin super-family which are present on the surface of endothelial cells. These molecules represent important markers of endothelial inflammation. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with (+/?)-alpha lipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by an increased oxidative stress status in the heart characterized by thiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation increase. The higher oxidative stress also modifies adhesion molecules expression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was increased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly greater in the renal endothelium of SHR. (+/?)-Alpha lipoic acid and (+)-alpha lipoic acid treatment significantly decreased TBARS levels, the nucleic acid oxidation and prevented adhesion molecules expression in cardiac and renal vascular endothelium. These data suggest that endothelial molecules may be used for studying the mechanisms of vascular injury on target organs of hypertension. The effects observed after treatment with (+)-alpha lipoic acid could open new perspectives for countering heart and kidney microvascular injury which represent a common feature in hypertensive end-organs damage.     

Pathogenesis of myocardial fibrosis in spontaneously hypertensive rats (SHR)

The pathomechanisms of myocardial fibrosis are incompletelyunderstood. Coronary microvessels (MV), interstitial reactionsand focal myocardial lesions characterized by morphologicalsigns of ischaemia were found in 39 spontaneous hypertensiverats (SHR) and 33 control rats aged 3, 13, 27, 52 and 78 weeks,using new morphological preparations and measuring methods.In the developing phase of spontaneous hypertension (SH) thenumerical and area densities (developed for up to 13 weeks)of MV were lower than at 3 weeks and lower than control. Thesame was true for the fibrotic tissue density. However, allvalues were increased in the manifest phase of SH (27–78weeks). The increase in interstitial tissue is topologicallyand causally related to pathological MV reactions that representmorphologically chronically increased contractions. Small MVthat mostly elude detection with conventional staining methodsare of particular importance. The first phase of manifest SH(27th–52nd week) is characterized by a generalized developmentof myocardial fibrosi the late phase (52nd–78th week)by a reinforced localized fibrosis that is attributable to theenhanced progression of focal ischaemic myocardial lesions.The septal region is not included in this phase. Thus, in thetwo phases of manifest SH, the pathomechanisms responsible forthe development of myocardial fibrosis must be different.     

胰激肽原酶对自发性高血压大鼠氧化损伤和心肌纤维化的影响

目的探讨胰激肽原酶对自发性高血压大鼠(SHR)抗氧化损伤和心肌纤维化的影响。方法15周龄雄性SHR大鼠24只,随机分成SHR对照组、胰激肽原酶小剂量组、大剂量组,每组8只。另取8只WKY大鼠作为正常血压对照组。小剂量组(7.2 U.kg-1.d-1)和大剂量组(14.4 U.kg-1.d-1)给予胰激肽原酶腹腔注射。治疗4 w后,测量各组收缩压(SBP)、左心室重量指数(LVM I)、心肌胶原容积分数(CVF)和心肌血管周围胶原面积(PVCA),同时测定血清中超氧化物岐化酶(SOD)、丙二醛(MDA)含量。结果治疗组SBP、CVF、PVCA与SHR对照组比较明显降低(P<0.05),仍未达到WKY组水平(P<0.05)。治疗组血清中SOD含量明显上升,MDA含量下降,与WKY组差异无显著性。结论胰激肽原酶能降低血压,减轻过氧化损伤,逆转心肌纤维化。且无明显毒副作用,有望成为治疗高血压左室肥厚新的有效药物。     

Alterations of phosphoinositide-specific phospholipase C and protein kinase C in the myocardium of spontaneously hypertensive rats

Summary In order to determine whether phosphoinositide metabolism is altered in hypertensive cardiac hypertrophy, phospholipase C (PLC) and protein kinase C activities were measured in hearts from 4- and 20-week-old spontaneously hypertensive rats (SHR) and age-matched, normotensive Wister-Kyoto rats (WKY). PLC activities were assayed using phosphatidylinositol (PI) and phosphatidylinositol-4,5-bisphosphate (PIP₂) as substrates to assess the substrate specificity. PI-hydrolyzing PLC activity (PI-PLC) was predominantly located in the cytosol, and its activity was similar in both strains. Membrane-bound PIP₂-hydrolyzing PLC activity (PIP₂-PLC) was significantly lower in 20-week-old SHR than in WKY, but there was no significant difference in soluble PIP₂-PLC. Protein kinase C activity was significantly elevated in 20-week-old SHR and Ca²⁺-phospholipid-dependent phosphorylation was observed in the proteins of molecular weight 26, 32, 43, and 95 KDa. In 4-week-old prehypertensive SHR, there were no significant differences in PI-PLC, PIP₂-PLC, or protein kinase C activities as compared with age-matched WKY. These data demonstrated that protein kinase C and membrane-bound PIP₂-PLC are altered during the period of hypertension development. These alterations may have important roles in the development or maintenance of hypertensive cardiac hypertrophy in SHR.Until April 31, 1990 N. Makita, Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-Ku Sapporo 060, Japan After May 1, 1990 N. Makita, Division of Nephrology, S-3223, Medical Center North, Vanderbilt University, Nashville. Tennessee 37232, USA     

A new model of Type 2 (non-insulin-dependent) diabetes mellitus in spontaneously hypertensive rats: diabetes induced by neonatal streptozotocin treatment

Summary This study was designed to develop an animal model of Type 2 (non-insulin-dependent) diabetes with persistent hypertension. Male spontaneously hypertensive rats were treated with 25.0, 37.5, 50.0, 62.5 or 75.0 mg/kg of streptozotocin given intraperitoneally at 2 days of age and maintained for 12 weeks. In the rats which received 50.0 mg/kg or more streptozotocin, overt hyperglycaemia gradually and consistently developed following incomplete recovery from an initial hyperglycaemia. Compared to vehicle-treated controls, body weight gain in these animals did not differ for the first 8 weeks; thereafter, it was slightly but significantly (p < 0.05) reduced. The animals treated with 25.0 or 37.5 mg/kg streptozotocin developed mild to moderate hyperglycaemia, but their body weight gain was similar to controls. The relationships between streptozotocin dose and metabolic responses (plasma glucose, glycosylated haemoglobin, urinary glucose, food intake, etc.) were clearly demonstrated. Systolic blood pressure rose with progressing age in both controls and streptozotocin-treated rats, irrespective of dosage or metabolic response. This new rat model of Type 2 diabetes associated with persistent hypertension may be useful in studying these combined effects on small and large vessels.     

白花丹参对自发性高血压大鼠心肌病变的影响

目的观察长期应用白花丹参水提物对自发性高血压大鼠心肌病变的影响及其机制。方法24只12周龄SHR大鼠随机分为3组：SHR组、白花丹参高剂量组（SMH）和白花丹参低剂量组（SML）。以WKY大鼠为阴性对照。灌胃给药12周后,记录24h清醒动脉血压、左心室重量指数（LVMI）,测血浆中一氧化氮合酶（cNOS）、一氧化氮（NO）、内皮素（ET）,左心室组织切片用HE和VanGieson染色,全自动图像分析系统进行分析．结果与WKY大鼠相比较,SHR组的血压、LVMI、心肌细胞直径（TDM）、心肌细胞面积（CA）、心肌组织胶原体积比例（CVF）和心肌血管周围胶原面积与管腔面积的比例（PVCA）显著升高[（190±19）／（143±11）mmHg、（4．71±0．54）mg／g、（32．35±5．87）μm、（560．53±90．62）μm^2,（8．13±0．71）％和（6．01±0．22）％],血浆ET水平显著升高,cNOS、NO、超氧化物歧化酶（SOD）均显著降低[（289．39±26．38）ng／ml、（54．41±6．25）μmol／L、（5．509±0．054）U／ml、（90．05±10．27）U／m1]。而白花丹参组,除收缩压外,各指标与SHR组比较差异均有统计学意义（P〈0．05）。结论白花丹参具有抑制自发性高血压大鼠心肌病变的作用。其机制可能与改善ET—NO系统和改善内皮功能障碍有关。     

地龙降压胶囊对自发性高血压大鼠肾胺酶表达的影响

目的:观察地龙降压胶囊对自发性高血压大鼠(SHR)肾胺酶表达的影响,以探讨地龙降压胶囊治疗原发性高血压的作用机制。方法:取24只8周龄雄性SHR,根据收缩压随机分为模型组(等容量蒸馏水灌胃)及地龙降压胶囊高、低剂量组(分别以地龙降压胶囊240mg/kg、120mg/kg灌胃),每组8只。另取8只WKY雄性大鼠作为正常对照组(等容量蒸馏水灌胃)。分别于连续给药前、给药后第2周、4周、6周、8周测定尾动脉收缩压。末次给药后,采用ELISA法检测大鼠血浆儿茶酚胺和血清肾胺酶含量。采用免疫组织化学法检测大鼠肾脏肾胺酶的表达。结果:地龙降压胶囊有效降低了SHR收缩压、血浆儿茶酚胺水平(P<0.05);升高了SHR肾胺酶水平(P<0.05)。结论:地龙降压胶囊能有效降低血压,其作用机制可能是通过调节肾胺酶表达水平,从而影响血浆儿茶酚胺水平实现的。