17-甲氧基-7-羟基-苯并呋喃查尔酮逆转压力超负荷大鼠心血管重构的作用及机制研究
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摘要
背景：
对于高血压，不单是血压升高造成心血管病危险，而应看作是多种病理生理异常构成的症候群，包括左心室重构、尿蛋白和内皮功能紊乱等，其主要病理生理学特征表现为压力超负荷（pressure overload）和心血管重构（cardiovascular remodeling），包括血管重构（vascular remodeling）和心脏重构（cardiac remodeling）。这些功能和结构改变如果不能及时有效地控制和治疗，后果将会更加复杂，甚至导致心源性猝死和心衰死亡。因此，是否能够和如何逆转高血压所致的心血管重构，已成为高血压治疗的关键，开发新的抗高血压和抗心血管重构的药物是心血管研究领域的热点之一。玉郎伞系蝶形花科植物疏叶崖豆Millettia pulchra (Benth.) Kurz var. Laxior (Dunn)Z.Wei的块根，是广西壮族的特色药材之一，具有广泛的心血管药理活性，17-甲氧基-7-羟基-苯并呋喃查尔酮（17-methoxyl-7-hydroxy-benzene-furanchalcone，简称MHBFC）是从玉郎伞中提取的黄酮化合物，课题组前期研究证实，MHBFC在体外具有较强的清除自由基、抗凝血能力，对H2O2和缺氧/复氧所致的心肌细胞损伤有明显的保护作用，在体内具有抗大鼠心肌缺血再灌注损伤的作用，该显著的心脏保护作用，让我们想到其对压力超负荷心血管重构是否亦有逆转作用。为此，本实验采用压力超负荷大鼠模型，研究MHBFC逆转压力超负荷大鼠心血管重构的作用及机制，为进一步的新药研发提供理论和实验依据。
目的：
研究MHBFC逆转压力超负荷大鼠心血管重构的作用及机制，为进一步的新药研发提供理论和实验依据。
方法：
雄性SD大鼠，体重130-160g。麻醉后于左肋弓下缘行纵切口，游离腹主动脉，将外径为0.7mm的小圆棒和腹主动脉平行放置，用丝线将其一起结扎，然后迅速抽出小圆棒，致使腹主动脉被缩窄到外径约0.7mm，形成腹主动脉缩窄模型，诱导心肌肥大和重构。假手术组大鼠只行手术通路，不缩窄腹主动脉，其余手术操作均和模型组相同。
第一部分MHBFC对压力超负荷大鼠心血管重构的作用
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）Lisinopril15mg/kg组；（4）MHBFC6mg/kg组；（5）MHBFC12mg/kg组。于手术后第4天开始灌胃给药，给药容积为0.2ml/l00g体重，每天给药1次，连续6周，假手术组和模型组仅给予等量溶媒。实验最后一天，采用多通道生物信号分析系统检测血流动力学和心功能的变化，Masson’s染色和HE染色观察心血管组织病理学改变，透射电子显微镜下观察心肌超微结构变化。RT-PCR检测心肌肥大的Marker基因-心房利钠肽（atrial natriureticpeptide，ANP）的表达。
第二部分：MHBFC逆转压力超负荷大鼠心血管重构的内皮机制研究
实验一基于内皮素系统的作用机制研究
本部分实验标本来自于实验的第一部分，分为4组：（1）假手术组；（2）模型组；（3）MHBFC6mg/kg组；（4）MHBFC12mg/kg组。收集到相关标本后，采用ELISA法测定血浆中内皮素-1（endothelin-1，ET-1）的含量，RT-PCR观察心肌组织ET-1和内皮素转化酶（endothelin converting enzyme，ECE）的表达，免疫组化法检测心肌组织内皮素A型受体（endothelin-1receptor A type，ETA）和内皮素B型受体（endothelin-1receptor B type，ETB）的表达。
实验二基于eNOS-NO信号通路的作用机制研究
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）MHBFC12mg/kg组；（4）左旋硝基精氨酸甲酯（NG-nitro-L-argininemethyl ester, L-NAME）50mg/kg（L-NAME50）组；（5）MHBFC12mg/kg+L-NAME50mg/kg （MHBFC12+L-NAME50）组。其中第（1）-（3）组同第一部分。实验最后一天，采用多通道生物信号分析系统检测大鼠血流动力学和心功能的变化，Masson’s染色和HE染色观察心肌组织的病理学改变，免疫组化法检测心肌组织内皮型一氧化氮合酶（endothelial nitricoxide synthase，eNOS）的蛋白表达，生化法检测血浆中一氧化氮（nitricoxide，NO）含量的变化。
实验三基于前列环素（prostacyclin, PGI2）的作用机制研究
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）MHBFC12mg/kg组；（4）吲哚美辛（indomethacin）2mg/kg（Indo2）组；（5）MHBFC12mg/kg+Indo2mg/kg（MHBFC12+Indo2）组。其中第（1）-（3）组同第一部分。实验最后一天，采用多通道生物信号分析系统观察血流动力学和心脏功能的变化，Masson’s染色和HE染色观察心肌组织病理学改变，ELISA法检测血浆中PGI2含量的变化。
结果：
第一部分MHBFC对压力超负荷大鼠心血管重构的作用
1.血压的变化：实验期间，假手术组大鼠尾动脉收缩压（systolic bloodpressure，SBP）基本保持稳定，模型组大鼠尾动脉SBP呈时间依赖性增加。经MHBFC6，12mg/kg治疗后，自试验第4周起，大鼠尾动脉SBP明显降低（P＜0.05或P＜0.01vs model group）。缩窄腹主动脉6周后，与假手术组相比，模型组大鼠颈动脉收缩压（aorta systolic blood pressure，ASBP）、颈动脉舒张压（aorta diastolic blood pressure，ADBP）和颈动脉平均动脉压（aorta mean blood pressure，AMBP）均明显增高（P＜0.01）。经MHBFC6，12mg/kg治疗后，大鼠颈动脉ASBP、ADBP和AMBP呈剂量相关性降低（P＜0.05或P＜0.01vs model group）。
2.心功能的改变：缩窄腹主动脉6周后，模型组大鼠的左室收缩压（leftventricular systolic pressure, LVSP）、左室压力最大上升速率（maximal rate ofleft ventricular systolicpressure，+dp/dtmax）和左室压力最大下降速率（maximalrate of left ventriculardiastolic pressure，-dp/dtmax）均明显增加（P＜0.01vssham group），而左室舒张末期压（left ventricular end diastolic pressure，LVEDP）明显降低（P＜0.01vs sham group）。而经MHBFC6，12mg/kg治疗后，大鼠的心室舒缩功能明显改善（P＜0.05或P＜0.01vs model group）。
3.心血管重构的程度：缩窄腹主动脉6周后，与假手术组相比，模型组大鼠的全心指数（heart weight/body weight，HW/BW）、左心指数（leftventricular weight/body weight，LVW/BW）、右心指数（right ventricularweight/body weight，RVW/BW）和肺指数（lung weight/body weight，LW/BW）均明显增加（P＜0.01），表明模型大鼠的心脏发生了大体上的重构。模型组大鼠心肌细胞横截面积、心肌间质胶原容积分数（collagen volume fraction，CVF）、心肌血管周围胶原面积（perivscular collagen area，PVCA）和心肌组织羟脯氨酸（hydroxyproline）的含量均明显增加（P＜0.01vs sham group）。血管HE染色检测结果发现，模型组大鼠腹主动脉的管腔总面积（lumenarea，LA）、血管总面积（total aorta area，TAA）、血管管壁横截面积（aortacross-section area，ACSA）、ACSA/TAA、血管平均直径（aorta diameter，AD）、血管管壁平均厚度（Media）、血管腔平均直径（Lumen）以及Media/Lumen等均明显增加（P＜0.01vs sham group），表明模型组大鼠的主动脉发生了明显的重构。另外，模型组大鼠心肌组织ANP mRNA的表达明显上调（P＜0.01vs sham group）。经MHBFC6，12mg/kg治疗后，心脏指数和肺指数明显降低，可明显抑制心肌细胞横截面积的增加，抑制CVF、PVCA和羟脯氨酸含量的升高（P＜0.05或P＜0.01vs model group），下调大鼠心肌组织ANP mRNA的表达（P＜0.05或P＜0.01vs modelgroup）。心肌超微结构检测发现，模型组大鼠心肌细胞发生了亚细胞结构的重构，表现为线粒体数量和体积的增加，经过MHBFC12mg/kg治疗后，大鼠心肌纤维呈有序地平行排列，肌小节由Z线均匀分隔，线粒体的形状呈较规则的卵圆形，且呈列分布在肌纤维之间，提示MHBFC可一定程度改善这种亚细胞结构的重构。
第二部分MHBFC逆转大鼠心血管重构的内皮机制研究
实验一基于内皮素系统的作用机制研究
缩窄腹主动脉6周后，与比假手术组相比，模型组大鼠血浆ET-1的含量明显升高（P＜0.01），心肌组织ET-1mRNA、ECE mRNA、ETA和ETB的表达均明显上调（P＜0.05或P＜0.01）。MHBFC6，12mg/kg治疗6周后，可明显抑制大鼠血浆ET-1的升高，下调大鼠心肌组织ET-1mRNA、ECE mRNA、ETA和ETB的表达（P＜0.05或P＜0.01vs model group）。血浆NO含量检测发现，模型组大鼠血浆NO含量明显低于假手术组（P＜0.01）。MHBFC6，12mg/kg可明显提高血浆中NO含量（P＜0.05或P＜0.01vs model group），并且血浆中NO的含量与RVW/BW、心肌羟脯氨酸含量、尾动脉SBP均呈现明显的负相关。
实验二基于eNOS-NO信号通路的作用机制研究
1.血压的变化：实验期间，L-NAME组大鼠尾动脉SBP随时间逐渐升高，与同期模型组的SBP相比有显著性差异（P＜0.05或P＜0.01）。与L-NAME组相比，合用MHBFC12mg/kg后，在第2、4、6周均能降低大鼠尾动脉SBP（P＜0.05或P＜0.01）。
2.心功能的改变：L-NAME组大鼠心室的收缩功能明显增强，而心室的舒张功能和顺应性明显降低（P＜0.01vs sham group）。合用MHBFC12mg/kg后，能明显降低ASBP和LVSP （P＜0.01vs L-NAME group），改善心肌的顺应性。
3.心脏重构的程度：缩窄腹主动脉6周后，L-NAME组大鼠的LVW/BW和RVW/BW明显增加，心肌细胞横截面积亦明显增加（P＜0.05或P＜0.01vs sham group），合用MHBFC12mg/kg后能明显改善心肌细胞的肥大（P＜0.01vs L-NAME group）。另外，L-NAME组大鼠心肌纤维化程度、心肌组织羟脯氨酸的含量明显增加（P＜0.01vs sham group），提示L-NAME诱发了比模型组更严重的胶原沉积，合用MHBFC12mg/kg可明显改善L-NAME导致的心肌纤维化，明显抑制心肌组织羟脯氨酸含量的增加（P＜0.01vs L-NAME group）。
4. eNOS-NO的改变：缩窄腹主动脉6周后，模型组大鼠心肌组织的eNOS蛋白表达水平与假手术组相比明显下调（P＜0.01），经过MHBFC12mg/kg治疗后，eNOS蛋白表达水平明显增加（P＜0.01vs model group）。L-NAME组大鼠心肌组织的eNOS蛋白表达被明显抑制，合用MHBFC12mg/kg后能明显提高被抑制的eNOS蛋白的表达（P＜0.01vs L-NAMEgroup）。L-NAME组大鼠血浆中的NO含量明显下降，合用MHBFC12mg/kg治疗后能明显增加血浆中NO的含量（P＜0.01vs L-NAME group）。
实验三基于前列环素（prostacyclin，PGI2）的作用机制研究
1.血压的变化：缩窄腹主动脉6周后，Indo2组大鼠的尾动脉SBP呈时间依赖性升高，ASBP也明显增加，合用MHBFC12mg/kg后能明显改善Indo诱导的高血流动力学状态（P＜0.05或P＜0.01vs Indo2group）。
2.心功能的改变：缩窄腹主动脉6周后，Indo2组大鼠的心脏收缩功能明显增加，心肌的顺应性明显下降，合用MHBFC12mg/kg后能明显抑制Indo引起的心肌收缩力的提高，改善心肌的顺应性。
3.心脏重构的程度：缩窄腹主动脉6周后，Indo2组大鼠的HW/BW、LVW/BW和RVW/BW明显增加（P＜0.01vs sham group），心肌细胞横截面积亦明显增加，合用MHBFC12mg/kg后能明显改善心肌细胞的肥大（P＜0.01vs Indo2group）。Indo2组大鼠心肌组织的CVF、PVCA和羟脯氨酸含量明显增加（P＜0.01vs sham group），合用MHBFC12mg/kg后能明显抑制CVF和PVCA的恶化（P＜0.05或P＜0.01vs Indo2group），明显抑制心肌组织羟脯氨酸含量的增高（P＜0.01vs Indo2group）。
4. PGI2含量的变化：缩窄腹主动脉6周后，模型组大鼠血浆中PGI2含量明显降低（P＜0.01vs sham group），经MHBFC12mg/kg治疗后能明显提高血浆中PGI2的含量（P＜0.01vs model group）。Indo2组大鼠血浆PGI2的含量亦明显降低，合用MHBFC12mg/kg后能明显提高血浆中PGI2的含量（P＜0.01vs Indo2group）。结论：
1. MHBFC6，12mg/kg可明显逆转压力超负荷大鼠的心血管重构，并且这种逆转作用呈一定的剂量依赖性；
2. MHBFC逆转心血管重构的作用机制可能与其恢复内皮细胞的分泌功能密切相关，表现为增加NO和PGI2的分泌，抑制ET-1的合成与分泌，抑制内皮素系统的活化。
Background：
Hypertension is a continuum that starts with a rise in blood pressure,evolves to left ventricular hypertrophy (LVH), proteinuria or endothelialdysfunction, and the major pathophysiological character is pressure overloadand cardiovascular remodeling, including vascular remodeling and cardiacremodeling. Insofar as it is not adequately treated or controlled, finally leads tothe development of complications, and the most relevant of which are stroke andheart failure. Therefore, whether and how to reverse the pressureoverload-induced ventricular remodeling is the key of the recent research. Thedevelopment of new antihypertensive and anticardiovascular remodeling drugsis the focus, which will be expected the decrease in morbidity and mortality ofhypertension. Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (MKL)is a traditional Chinese medicinal herb that is extensively distributed in theGuangxi Province of China, and17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) is a flavonoid monomer that was originally isolatedfrom a60%ethanol extract from MKL roots. Previous studies havedemonstrated that MHBFC could scavenge hydroxyl radicals and oxyradicals,enhance the cardiocyte survival rate in H2O2and hypoxia/reoxygenation injury,and protect the heart against myocardial ischemia in vitro and in vivo. Based on the above information, we hypothesized that MHBFC might be effective in thetreatment of hypertensive heart disease. Here, for the first time, we were toinvestigate its effect on cardiovascular remodeling induced by pressure overloadas well as the potential mechanisms, which provide the experimental evidenceand theoretical support for further development of MHBFC on reversingcardiovascular remodeling.
Objective:
To study the reverse effects and mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in rats, which provid theexperimental evidence and theoretical support for further development ofMHBFC on reversing cardiovascular remodeling.
Methods:
Male Sprague–Dawley rats with a body weight of130–160g wereanesthetized under sterile conditions, and the abdominal aorta above the kidneyswas exposed through a abdominal incision and constricted at the suprarenallevel by a4-0silk suture tied around both the aorta and a blunted22-gaugeneedle, which was then pulled out. A similar procedure was performed for shamgroup without the ligature.
PartⅠ The protective effects of MHBFC on cardiovascular system inpressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6)：(1) shamgroup;(2) model group;(3) Lisinopril15mg/kg group;(4) MHBFC6mg/kggroup;(5) MHBFC12mg/kg group. The drugs were dissolved in distilled waterand orally administered once a day in0.2mL/100g body weight for6weeksfrom the fourth day after surgery. At the end of the experiment, a biologicalsignal quantitative analytical system was used to evaluate the hemodynamics and heart function, the histological changes were investigated by HE andMasson’s stain, the transmission electron microscopes was used to observe themyocardium ultrastructure. RT-PCR method was used to measure the expressionof atrial natriuretic peptide (ANP) mRNA in myocardial tissue.
Part Ⅱ Studies of the endothelial mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in rats
Experiment1Studies of endothelial mechanisms of MHBFC base on theendothelin system in pressure-overload rats
The samples obtained from the first part of the experiment were dividedinto4groups:(1) sham group;(2) model group;(3) Lisinopril15mg/kg group;(4) MHBFC12mg/kg group. ELISA was used to determine the plasma ET-1content, RT-PCR method was used to measure the cardiac ET-1and ECE mRNAexpressions, immunochemical method was used to evaluate the ETAand ETBexpressions in myocardial tissue.
Experiment2Studies of endothelial mechanisms of MHBFC base on theeNOS-NO signal pathway in pressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6):(1) shamgroup;(2) model group;(3) MHBFC12mg/kg group;(4) L-NAME50mg/kggroup (L-NAME50group);(5) L-NAME50mg/kg+MHBFC12mg/kg group(L-NAME50+MHBFC12group). At the end of the experiment, a biologicalsignal quantitative analytical system was used to evaluate the hemodynamicsand heart function, and the histological changes were investigated by HE andMasson’s stain. The immunochemical method was used to evaluate the cardiaceNOS expression, and biochemical method was used to determine plasma NOcontent.
Experiment3Studies of endothelial mechanisms of MHBFC base on thePGI2in pressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6)：(1) shamgroup;(2) model group;(3) MHBFC12mg/kg group;(4) indomethacin2mg/kggroup (Indo2group);(5) indomethacin2mg/kg+MHBFC12mg/kg group(Indo2+MHBFC12group). At the end of the experiment, a biological signalquantitative analytical system was used to evaluate the hemodynamics and heartfunction, the histological changes were investigated by HE and Masson’s stain.ELISA was used to determine the plasma PGI2content.
Results：
PartⅠ The protective effects of MHBFC on cardiovascular system inpressure-overload rats
1. The change of blood pressure: During the time course, the tail arterialsystolic blood pressure (SBP) in sham group rats maintained at the baseline level,the tail arterial SBP in model group rats increased significantly with atime-dependent manner. After treatment with MHBFC6,12mg/kg, the increaseof tail arterial SBP was inhibited markedly from the fourth week (P＜0.05or P＜0.01vs model group).At sixth week after aortic banding, the carotidASBP,ADBP and AMBP in model group rats increased significantly (P＜0.01), whencompared with the sham group. After treatment with MHBFC6,12mg/kg, theincrease of carotid ASBP, ADBP and AMBP were inhibited significantly (P＜0.05or P＜0.01vs model group).
2. The change of heart function: At sixth week after aortic banding, the LVSPand±dp/dtmaxin model group rats increased significantly (P＜0.01vs shamgroup), while LVEDP decreased significantly (P＜0.01vs sham group). Aftertreatment with MHBFC6,12mg/kg, the left ventricular systolic and diastolicfunction were ameliorated significantly (P＜0.05or P＜0.01vs model group).
3. Cardiovascular remodeling: At sixth week after aortic banding, the heartweight/body weight (HW/BW), left ventricular weight/body weight (LVW/BW),right ventricular weight/body weight (RVW/BW), lung weight/body weight(LW/BW), total aorta area (TAA), lumen area (LA), aorta cross-section area(ACSA), ACSA/TAA, aorta diameter (AD), media, lumen and media/lumen inmodel group rats increased significantly (P＜0.01), when compared with shamgroup, indicating a morphological remodeling of heart and aorta. Thecardiomyocyte cross-sectional area, CVF, PVCA and cardiac tissuehydroxyproline in model group rats increased significantly (P＜0.01vs shamgroup). Furthermore, the ANP mRNA expression increased significantly (P＜0.01vs sham group). After treatment with MHBFC6,12mg/kg, the HW/BW,LVW/BW, RVW/BW, LW/BW decreased significantly, cardiomyocytecross-section area, CVF, PVCA, hydroxyproline content in cardiac tissue werereversed, respectively (P＜0.05or P＜0.01vs model group). Myocardial tissueANP mRNA expression was downregulated significantly (P＜0.05or P＜0.01vs model group). Ultrastructural examination revealed that the ultrastructure ofthe cardiomyocytes in model group rats presented mitochondrial changes,characterized by diffuse mild to moderate increase in size (hypertrophy) andnumber (hyperplasia), focally forming several rows of enlarged mitochondriaseparating the myofibrils. Many mitochondria had the appearance of elongatedgiant mitochondria. Longitudinally oriented cristae, either parallel to the longaxis of the mitochondrion or irregular and concentric, were observed in manyareas. After treatment with MHBFC12mg/kg, the cardiomyocytes showedalmost uniform parallel myofibril arrangement. Z-lines dividing the sarcomereswere linear and perpendicular to the myofilaments. Myofibrils alternated withfew rows of ovoid mitochondria.
Part Ⅱ Studies of the endothelial mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in ratsExperiment1Studies of endothelial mechanisms of MHBFC base on theendothelin system in pressure-overload rats
At sixth week after aortic banding, the plasma ET-1content was increased,ET-1mRNA, ECE mRNA and ETA, ETBprotein expressions in the myocardialtissue were upregulated in model group rats compared with those in sham grouprats (P＜0.05or P＜0.01). After treatment with MHBFC6,12mg/kg for6weeks, plasma ET-1content was decreased significantly (P＜0.01vs modelgroup), and the upregulation of myocardial tissue ET-1mRNA, ECE mRNA andETA, ETBprotein expressions were inhibited markedly (P＜0.05or P＜0.01vsmodel group).
At sixth week after aortic banding, plasma NO content was decreased inmodel group compared with that in sham group (P＜0.01). Treatment withMHBFC6,12mg/kg increased the plasma NO content significantly, and thesignificant negative linear correlations were found between RVW/BW, cardiactissue hydroxyproline, SBP and plasma NO.
Experiment2Studies of endothelial mechanisms of MHBFC base on theeNOS-NO signal pathway in pressure-overload rats
1. The change of blood pressure: The tail arterial SBP in L-NAME group ratsincreased significantly with a time-dependent manner compared with that inmodel group rats, respectively (P<0.05or P<0.0l). Combined with MHBFC12mg/kg, the tail arterial SBP in the2nd,4th,6th weeks decreased significantlycompared with that in L-NAME group rats, respectively (P<0.05or P<0.0l).
2. The change of heart function: After6weeks of NO synthase inhibition, anenhanced contractility but a reduced diastolic compliance were taken place in L-NAME group rats (P＜0.01vs sham group), MHBFC could significantameliorate the LV function, and the ASBP and LVSP decreased significantly(P＜0.01vs L-NAME group).
3. Cardiac remodeling: At sixth week after aortic banding, the LVW/BW,RVW/BW and cardiomyocytes cross-section increased significantly in L-NAMEgroup rats (P＜0.05or P＜0.01vs sham group). The combination of MHBFC12mg/kg with L-NAME ameliorated cardiac hypertrophy significantly (P＜0.01vs L-NAME group). Histological examination demonstrated that both CVF,PVCA and myocardial tissue hydroxyproline increased significantly inL-NAME group compared with that in sham group rats (P＜0.01), and thecombination of MHBFC12mg/kg with L-NAME decreased cardiac tissuehydroxyproline significantly (P＜0.01vs L-NAME group).
4. The change of eNOS-NO: At sixth week after aortic banding, the eNOSprotein expression level was decreased significantly in mode group rats (P＜0.01vs sham group). Treatment with MHBFC12mg/kg, the eNOS proteinexpression level was increased significantly (P＜0.01vs model group). TheeNOS protein expression level was decreased significantly in L-NAME grouprats, but combination with MHBFC12mg/kg, the eNOS protein expressionlevel was increased significantly (P＜0.01vs L-NAME group). The plasma NOwas decreased significantly in L-NAME group rats, but combination withMHBFC12mg/kg, the plasma NO was increased significantly (P＜0.01vsL-NAME group).
Experiment3Studies of endothelial mechanisms of MHBFC base on thePGI2in pressure-overload rats
1. The change of blood pressure: At sixth week after aortic banding, the tailartery SBP and ASBP in Indo2group rats increased significantly with a time-dependent manner. Combination with MHBFC12mg/kg amelioratedindomethacin induced severe hemodynamics significantly (P＜0.05or P＜0.01vs Indo2group).
2. The change of heart function: At sixth week after aortic banding, the cardiaccontractility in Indo2group rats increased significantly, but a reduced cardiacdiastolic compliance significantly. Combined with MHBFC12mg/kg inhibitedthe increase of cardiac contractility, ameliorated cardiac compliance.
3. Cardiac remodeling: At sixth week after aortic banding, HW/BW, LVW/BW,RVW/BW and cardiomyocytes cross-section increased significantly in Indo2group (P＜0.01vs sham group). Combination with MHBFC12mg/kgameliorated cardiomyocytes hypertrophy significantly (P＜0.01vs Indo2group). Compared with sham group, the CVF, PVCA and hydroxyprolineincreased significantly in Indo2group (P＜0.01), and combination withMHBFC12mg/kg inhibited the deterioration of CVF and PVCA (P＜0.05or P＜0.01vs Indo2group), inhibited the increase of cardiac hydroxyproline (P＜0.01vs Indo2group).
4. The change of plasma PGI2content: At sixth week after aortic banding, theplasma PGI2content decreased significantly in model group rats (P＜0.01vssham group). Long-term treatment with MHBFC12mg/kg increased plasmaPGI2significantly (P＜0.01vs model group). Chronic administration of indodecreased plasma PGI2content significantly, and combination with MHBFC12mg/kg inhibited the decrease of plasma PGI2content significantly (P＜0.01vsIndo2group).
Conclusions:
1. MHBFC6,12mg/kg can significantly reverse pressure-overloadcardiovascular remodeling induced by abdominal aorta binding in rats with a certain extent of dose-dependent manner;
2. The protective mechanism of MHBFC on cardiovascular system inpressure-overload rats may be related to its regulation of endothelial function,augmenting NO and PGI2secretion, and inhibiting ET-1biosynthesis andsecretion, and ET-1system activation.
对于高血压，不单是血压升高造成心血管病危险，而应看作是多种病理生理异常构成的症候群，包括左心室重构、尿蛋白和内皮功能紊乱等，其主要病理生理学特征表现为压力超负荷（pressure overload）和心血管重构（cardiovascular remodeling），包括血管重构（vascular remodeling）和心脏重构（cardiac remodeling）。这些功能和结构改变如果不能及时有效地控制和治疗，后果将会更加复杂，甚至导致心源性猝死和心衰死亡。因此，是否能够和如何逆转高血压所致的心血管重构，已成为高血压治疗的关键，开发新的抗高血压和抗心血管重构的药物是心血管研究领域的热点之一。玉郎伞系蝶形花科植物疏叶崖豆Millettia pulchra (Benth.) Kurz var. Laxior (Dunn)Z.Wei的块根，是广西壮族的特色药材之一，具有广泛的心血管药理活性，17-甲氧基-7-羟基-苯并呋喃查尔酮（17-methoxyl-7-hydroxy-benzene-furanchalcone，简称MHBFC）是从玉郎伞中提取的黄酮化合物，课题组前期研究证实，MHBFC在体外具有较强的清除自由基、抗凝血能力，对H2O2和缺氧/复氧所致的心肌细胞损伤有明显的保护作用，在体内具有抗大鼠心肌缺血再灌注损伤的作用，该显著的心脏保护作用，让我们想到其对压力超负荷心血管重构是否亦有逆转作用。为此，本实验采用压力超负荷大鼠模型，研究MHBFC逆转压力超负荷大鼠心血管重构的作用及机制，为进一步的新药研发提供理论和实验依据。
目的：
研究MHBFC逆转压力超负荷大鼠心血管重构的作用及机制，为进一步的新药研发提供理论和实验依据。
方法：
雄性SD大鼠，体重130-160g。麻醉后于左肋弓下缘行纵切口，游离腹主动脉，将外径为0.7mm的小圆棒和腹主动脉平行放置，用丝线将其一起结扎，然后迅速抽出小圆棒，致使腹主动脉被缩窄到外径约0.7mm，形成腹主动脉缩窄模型，诱导心肌肥大和重构。假手术组大鼠只行手术通路，不缩窄腹主动脉，其余手术操作均和模型组相同。
第一部分MHBFC对压力超负荷大鼠心血管重构的作用
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）Lisinopril15mg/kg组；（4）MHBFC6mg/kg组；（5）MHBFC12mg/kg组。于手术后第4天开始灌胃给药，给药容积为0.2ml/l00g体重，每天给药1次，连续6周，假手术组和模型组仅给予等量溶媒。实验最后一天，采用多通道生物信号分析系统检测血流动力学和心功能的变化，Masson’s染色和HE染色观察心血管组织病理学改变，透射电子显微镜下观察心肌超微结构变化。RT-PCR检测心肌肥大的Marker基因-心房利钠肽（atrial natriureticpeptide，ANP）的表达。
第二部分：MHBFC逆转压力超负荷大鼠心血管重构的内皮机制研究
实验一基于内皮素系统的作用机制研究
本部分实验标本来自于实验的第一部分，分为4组：（1）假手术组；（2）模型组；（3）MHBFC6mg/kg组；（4）MHBFC12mg/kg组。收集到相关标本后，采用ELISA法测定血浆中内皮素-1（endothelin-1，ET-1）的含量，RT-PCR观察心肌组织ET-1和内皮素转化酶（endothelin converting enzyme，ECE）的表达，免疫组化法检测心肌组织内皮素A型受体（endothelin-1receptor A type，ETA）和内皮素B型受体（endothelin-1receptor B type，ETB）的表达。
实验二基于eNOS-NO信号通路的作用机制研究
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）MHBFC12mg/kg组；（4）左旋硝基精氨酸甲酯（NG-nitro-L-argininemethyl ester, L-NAME）50mg/kg（L-NAME50）组；（5）MHBFC12mg/kg+L-NAME50mg/kg （MHBFC12+L-NAME50）组。其中第（1）-（3）组同第一部分。实验最后一天，采用多通道生物信号分析系统检测大鼠血流动力学和心功能的变化，Masson’s染色和HE染色观察心肌组织的病理学改变，免疫组化法检测心肌组织内皮型一氧化氮合酶（endothelial nitricoxide synthase，eNOS）的蛋白表达，生化法检测血浆中一氧化氮（nitricoxide，NO）含量的变化。
实验三基于前列环素（prostacyclin, PGI2）的作用机制研究
术后，大鼠随机分为5组，每组6只：（1）假手术组；（2）模型组；（3）MHBFC12mg/kg组；（4）吲哚美辛（indomethacin）2mg/kg（Indo2）组；（5）MHBFC12mg/kg+Indo2mg/kg（MHBFC12+Indo2）组。其中第（1）-（3）组同第一部分。实验最后一天，采用多通道生物信号分析系统观察血流动力学和心脏功能的变化，Masson’s染色和HE染色观察心肌组织病理学改变，ELISA法检测血浆中PGI2含量的变化。
结果：
第一部分MHBFC对压力超负荷大鼠心血管重构的作用
1.血压的变化：实验期间，假手术组大鼠尾动脉收缩压（systolic bloodpressure，SBP）基本保持稳定，模型组大鼠尾动脉SBP呈时间依赖性增加。经MHBFC6，12mg/kg治疗后，自试验第4周起，大鼠尾动脉SBP明显降低（P＜0.05或P＜0.01vs model group）。缩窄腹主动脉6周后，与假手术组相比，模型组大鼠颈动脉收缩压（aorta systolic blood pressure，ASBP）、颈动脉舒张压（aorta diastolic blood pressure，ADBP）和颈动脉平均动脉压（aorta mean blood pressure，AMBP）均明显增高（P＜0.01）。经MHBFC6，12mg/kg治疗后，大鼠颈动脉ASBP、ADBP和AMBP呈剂量相关性降低（P＜0.05或P＜0.01vs model group）。
2.心功能的改变：缩窄腹主动脉6周后，模型组大鼠的左室收缩压（leftventricular systolic pressure, LVSP）、左室压力最大上升速率（maximal rate ofleft ventricular systolicpressure，+dp/dtmax）和左室压力最大下降速率（maximalrate of left ventriculardiastolic pressure，-dp/dtmax）均明显增加（P＜0.01vssham group），而左室舒张末期压（left ventricular end diastolic pressure，LVEDP）明显降低（P＜0.01vs sham group）。而经MHBFC6，12mg/kg治疗后，大鼠的心室舒缩功能明显改善（P＜0.05或P＜0.01vs model group）。
3.心血管重构的程度：缩窄腹主动脉6周后，与假手术组相比，模型组大鼠的全心指数（heart weight/body weight，HW/BW）、左心指数（leftventricular weight/body weight，LVW/BW）、右心指数（right ventricularweight/body weight，RVW/BW）和肺指数（lung weight/body weight，LW/BW）均明显增加（P＜0.01），表明模型大鼠的心脏发生了大体上的重构。模型组大鼠心肌细胞横截面积、心肌间质胶原容积分数（collagen volume fraction，CVF）、心肌血管周围胶原面积（perivscular collagen area，PVCA）和心肌组织羟脯氨酸（hydroxyproline）的含量均明显增加（P＜0.01vs sham group）。血管HE染色检测结果发现，模型组大鼠腹主动脉的管腔总面积（lumenarea，LA）、血管总面积（total aorta area，TAA）、血管管壁横截面积（aortacross-section area，ACSA）、ACSA/TAA、血管平均直径（aorta diameter，AD）、血管管壁平均厚度（Media）、血管腔平均直径（Lumen）以及Media/Lumen等均明显增加（P＜0.01vs sham group），表明模型组大鼠的主动脉发生了明显的重构。另外，模型组大鼠心肌组织ANP mRNA的表达明显上调（P＜0.01vs sham group）。经MHBFC6，12mg/kg治疗后，心脏指数和肺指数明显降低，可明显抑制心肌细胞横截面积的增加，抑制CVF、PVCA和羟脯氨酸含量的升高（P＜0.05或P＜0.01vs model group），下调大鼠心肌组织ANP mRNA的表达（P＜0.05或P＜0.01vs modelgroup）。心肌超微结构检测发现，模型组大鼠心肌细胞发生了亚细胞结构的重构，表现为线粒体数量和体积的增加，经过MHBFC12mg/kg治疗后，大鼠心肌纤维呈有序地平行排列，肌小节由Z线均匀分隔，线粒体的形状呈较规则的卵圆形，且呈列分布在肌纤维之间，提示MHBFC可一定程度改善这种亚细胞结构的重构。
第二部分MHBFC逆转大鼠心血管重构的内皮机制研究
实验一基于内皮素系统的作用机制研究
缩窄腹主动脉6周后，与比假手术组相比，模型组大鼠血浆ET-1的含量明显升高（P＜0.01），心肌组织ET-1mRNA、ECE mRNA、ETA和ETB的表达均明显上调（P＜0.05或P＜0.01）。MHBFC6，12mg/kg治疗6周后，可明显抑制大鼠血浆ET-1的升高，下调大鼠心肌组织ET-1mRNA、ECE mRNA、ETA和ETB的表达（P＜0.05或P＜0.01vs model group）。血浆NO含量检测发现，模型组大鼠血浆NO含量明显低于假手术组（P＜0.01）。MHBFC6，12mg/kg可明显提高血浆中NO含量（P＜0.05或P＜0.01vs model group），并且血浆中NO的含量与RVW/BW、心肌羟脯氨酸含量、尾动脉SBP均呈现明显的负相关。
实验二基于eNOS-NO信号通路的作用机制研究
1.血压的变化：实验期间，L-NAME组大鼠尾动脉SBP随时间逐渐升高，与同期模型组的SBP相比有显著性差异（P＜0.05或P＜0.01）。与L-NAME组相比，合用MHBFC12mg/kg后，在第2、4、6周均能降低大鼠尾动脉SBP（P＜0.05或P＜0.01）。
2.心功能的改变：L-NAME组大鼠心室的收缩功能明显增强，而心室的舒张功能和顺应性明显降低（P＜0.01vs sham group）。合用MHBFC12mg/kg后，能明显降低ASBP和LVSP （P＜0.01vs L-NAME group），改善心肌的顺应性。
3.心脏重构的程度：缩窄腹主动脉6周后，L-NAME组大鼠的LVW/BW和RVW/BW明显增加，心肌细胞横截面积亦明显增加（P＜0.05或P＜0.01vs sham group），合用MHBFC12mg/kg后能明显改善心肌细胞的肥大（P＜0.01vs L-NAME group）。另外，L-NAME组大鼠心肌纤维化程度、心肌组织羟脯氨酸的含量明显增加（P＜0.01vs sham group），提示L-NAME诱发了比模型组更严重的胶原沉积，合用MHBFC12mg/kg可明显改善L-NAME导致的心肌纤维化，明显抑制心肌组织羟脯氨酸含量的增加（P＜0.01vs L-NAME group）。
4. eNOS-NO的改变：缩窄腹主动脉6周后，模型组大鼠心肌组织的eNOS蛋白表达水平与假手术组相比明显下调（P＜0.01），经过MHBFC12mg/kg治疗后，eNOS蛋白表达水平明显增加（P＜0.01vs model group）。L-NAME组大鼠心肌组织的eNOS蛋白表达被明显抑制，合用MHBFC12mg/kg后能明显提高被抑制的eNOS蛋白的表达（P＜0.01vs L-NAMEgroup）。L-NAME组大鼠血浆中的NO含量明显下降，合用MHBFC12mg/kg治疗后能明显增加血浆中NO的含量（P＜0.01vs L-NAME group）。
实验三基于前列环素（prostacyclin，PGI2）的作用机制研究
1.血压的变化：缩窄腹主动脉6周后，Indo2组大鼠的尾动脉SBP呈时间依赖性升高，ASBP也明显增加，合用MHBFC12mg/kg后能明显改善Indo诱导的高血流动力学状态（P＜0.05或P＜0.01vs Indo2group）。
2.心功能的改变：缩窄腹主动脉6周后，Indo2组大鼠的心脏收缩功能明显增加，心肌的顺应性明显下降，合用MHBFC12mg/kg后能明显抑制Indo引起的心肌收缩力的提高，改善心肌的顺应性。
3.心脏重构的程度：缩窄腹主动脉6周后，Indo2组大鼠的HW/BW、LVW/BW和RVW/BW明显增加（P＜0.01vs sham group），心肌细胞横截面积亦明显增加，合用MHBFC12mg/kg后能明显改善心肌细胞的肥大（P＜0.01vs Indo2group）。Indo2组大鼠心肌组织的CVF、PVCA和羟脯氨酸含量明显增加（P＜0.01vs sham group），合用MHBFC12mg/kg后能明显抑制CVF和PVCA的恶化（P＜0.05或P＜0.01vs Indo2group），明显抑制心肌组织羟脯氨酸含量的增高（P＜0.01vs Indo2group）。
4. PGI2含量的变化：缩窄腹主动脉6周后，模型组大鼠血浆中PGI2含量明显降低（P＜0.01vs sham group），经MHBFC12mg/kg治疗后能明显提高血浆中PGI2的含量（P＜0.01vs model group）。Indo2组大鼠血浆PGI2的含量亦明显降低，合用MHBFC12mg/kg后能明显提高血浆中PGI2的含量（P＜0.01vs Indo2group）。结论：
1. MHBFC6，12mg/kg可明显逆转压力超负荷大鼠的心血管重构，并且这种逆转作用呈一定的剂量依赖性；
2. MHBFC逆转心血管重构的作用机制可能与其恢复内皮细胞的分泌功能密切相关，表现为增加NO和PGI2的分泌，抑制ET-1的合成与分泌，抑制内皮素系统的活化。
Background：
Hypertension is a continuum that starts with a rise in blood pressure,evolves to left ventricular hypertrophy (LVH), proteinuria or endothelialdysfunction, and the major pathophysiological character is pressure overloadand cardiovascular remodeling, including vascular remodeling and cardiacremodeling. Insofar as it is not adequately treated or controlled, finally leads tothe development of complications, and the most relevant of which are stroke andheart failure. Therefore, whether and how to reverse the pressureoverload-induced ventricular remodeling is the key of the recent research. Thedevelopment of new antihypertensive and anticardiovascular remodeling drugsis the focus, which will be expected the decrease in morbidity and mortality ofhypertension. Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (MKL)is a traditional Chinese medicinal herb that is extensively distributed in theGuangxi Province of China, and17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) is a flavonoid monomer that was originally isolatedfrom a60%ethanol extract from MKL roots. Previous studies havedemonstrated that MHBFC could scavenge hydroxyl radicals and oxyradicals,enhance the cardiocyte survival rate in H2O2and hypoxia/reoxygenation injury,and protect the heart against myocardial ischemia in vitro and in vivo. Based on the above information, we hypothesized that MHBFC might be effective in thetreatment of hypertensive heart disease. Here, for the first time, we were toinvestigate its effect on cardiovascular remodeling induced by pressure overloadas well as the potential mechanisms, which provide the experimental evidenceand theoretical support for further development of MHBFC on reversingcardiovascular remodeling.
Objective:
To study the reverse effects and mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in rats, which provid theexperimental evidence and theoretical support for further development ofMHBFC on reversing cardiovascular remodeling.
Methods:
Male Sprague–Dawley rats with a body weight of130–160g wereanesthetized under sterile conditions, and the abdominal aorta above the kidneyswas exposed through a abdominal incision and constricted at the suprarenallevel by a4-0silk suture tied around both the aorta and a blunted22-gaugeneedle, which was then pulled out. A similar procedure was performed for shamgroup without the ligature.
PartⅠ The protective effects of MHBFC on cardiovascular system inpressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6)：(1) shamgroup;(2) model group;(3) Lisinopril15mg/kg group;(4) MHBFC6mg/kggroup;(5) MHBFC12mg/kg group. The drugs were dissolved in distilled waterand orally administered once a day in0.2mL/100g body weight for6weeksfrom the fourth day after surgery. At the end of the experiment, a biologicalsignal quantitative analytical system was used to evaluate the hemodynamics and heart function, the histological changes were investigated by HE andMasson’s stain, the transmission electron microscopes was used to observe themyocardium ultrastructure. RT-PCR method was used to measure the expressionof atrial natriuretic peptide (ANP) mRNA in myocardial tissue.
Part Ⅱ Studies of the endothelial mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in rats
Experiment1Studies of endothelial mechanisms of MHBFC base on theendothelin system in pressure-overload rats
The samples obtained from the first part of the experiment were dividedinto4groups:(1) sham group;(2) model group;(3) Lisinopril15mg/kg group;(4) MHBFC12mg/kg group. ELISA was used to determine the plasma ET-1content, RT-PCR method was used to measure the cardiac ET-1and ECE mRNAexpressions, immunochemical method was used to evaluate the ETAand ETBexpressions in myocardial tissue.
Experiment2Studies of endothelial mechanisms of MHBFC base on theeNOS-NO signal pathway in pressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6):(1) shamgroup;(2) model group;(3) MHBFC12mg/kg group;(4) L-NAME50mg/kggroup (L-NAME50group);(5) L-NAME50mg/kg+MHBFC12mg/kg group(L-NAME50+MHBFC12group). At the end of the experiment, a biologicalsignal quantitative analytical system was used to evaluate the hemodynamicsand heart function, and the histological changes were investigated by HE andMasson’s stain. The immunochemical method was used to evaluate the cardiaceNOS expression, and biochemical method was used to determine plasma NOcontent.
Experiment3Studies of endothelial mechanisms of MHBFC base on thePGI2in pressure-overload rats
After surgery, the rats were divided randomly into5groups (n=6)：(1) shamgroup;(2) model group;(3) MHBFC12mg/kg group;(4) indomethacin2mg/kggroup (Indo2group);(5) indomethacin2mg/kg+MHBFC12mg/kg group(Indo2+MHBFC12group). At the end of the experiment, a biological signalquantitative analytical system was used to evaluate the hemodynamics and heartfunction, the histological changes were investigated by HE and Masson’s stain.ELISA was used to determine the plasma PGI2content.
Results：
PartⅠ The protective effects of MHBFC on cardiovascular system inpressure-overload rats
1. The change of blood pressure: During the time course, the tail arterialsystolic blood pressure (SBP) in sham group rats maintained at the baseline level,the tail arterial SBP in model group rats increased significantly with atime-dependent manner. After treatment with MHBFC6,12mg/kg, the increaseof tail arterial SBP was inhibited markedly from the fourth week (P＜0.05or P＜0.01vs model group).At sixth week after aortic banding, the carotidASBP,ADBP and AMBP in model group rats increased significantly (P＜0.01), whencompared with the sham group. After treatment with MHBFC6,12mg/kg, theincrease of carotid ASBP, ADBP and AMBP were inhibited significantly (P＜0.05or P＜0.01vs model group).
2. The change of heart function: At sixth week after aortic banding, the LVSPand±dp/dtmaxin model group rats increased significantly (P＜0.01vs shamgroup), while LVEDP decreased significantly (P＜0.01vs sham group). Aftertreatment with MHBFC6,12mg/kg, the left ventricular systolic and diastolicfunction were ameliorated significantly (P＜0.05or P＜0.01vs model group).
3. Cardiovascular remodeling: At sixth week after aortic banding, the heartweight/body weight (HW/BW), left ventricular weight/body weight (LVW/BW),right ventricular weight/body weight (RVW/BW), lung weight/body weight(LW/BW), total aorta area (TAA), lumen area (LA), aorta cross-section area(ACSA), ACSA/TAA, aorta diameter (AD), media, lumen and media/lumen inmodel group rats increased significantly (P＜0.01), when compared with shamgroup, indicating a morphological remodeling of heart and aorta. Thecardiomyocyte cross-sectional area, CVF, PVCA and cardiac tissuehydroxyproline in model group rats increased significantly (P＜0.01vs shamgroup). Furthermore, the ANP mRNA expression increased significantly (P＜0.01vs sham group). After treatment with MHBFC6,12mg/kg, the HW/BW,LVW/BW, RVW/BW, LW/BW decreased significantly, cardiomyocytecross-section area, CVF, PVCA, hydroxyproline content in cardiac tissue werereversed, respectively (P＜0.05or P＜0.01vs model group). Myocardial tissueANP mRNA expression was downregulated significantly (P＜0.05or P＜0.01vs model group). Ultrastructural examination revealed that the ultrastructure ofthe cardiomyocytes in model group rats presented mitochondrial changes,characterized by diffuse mild to moderate increase in size (hypertrophy) andnumber (hyperplasia), focally forming several rows of enlarged mitochondriaseparating the myofibrils. Many mitochondria had the appearance of elongatedgiant mitochondria. Longitudinally oriented cristae, either parallel to the longaxis of the mitochondrion or irregular and concentric, were observed in manyareas. After treatment with MHBFC12mg/kg, the cardiomyocytes showedalmost uniform parallel myofibril arrangement. Z-lines dividing the sarcomereswere linear and perpendicular to the myofilaments. Myofibrils alternated withfew rows of ovoid mitochondria.
Part Ⅱ Studies of the endothelial mechanisms of MHBFC on pressureoverload-induced cardiovascular remodeling in ratsExperiment1Studies of endothelial mechanisms of MHBFC base on theendothelin system in pressure-overload rats
At sixth week after aortic banding, the plasma ET-1content was increased,ET-1mRNA, ECE mRNA and ETA, ETBprotein expressions in the myocardialtissue were upregulated in model group rats compared with those in sham grouprats (P＜0.05or P＜0.01). After treatment with MHBFC6,12mg/kg for6weeks, plasma ET-1content was decreased significantly (P＜0.01vs modelgroup), and the upregulation of myocardial tissue ET-1mRNA, ECE mRNA andETA, ETBprotein expressions were inhibited markedly (P＜0.05or P＜0.01vsmodel group).
At sixth week after aortic banding, plasma NO content was decreased inmodel group compared with that in sham group (P＜0.01). Treatment withMHBFC6,12mg/kg increased the plasma NO content significantly, and thesignificant negative linear correlations were found between RVW/BW, cardiactissue hydroxyproline, SBP and plasma NO.
Experiment2Studies of endothelial mechanisms of MHBFC base on theeNOS-NO signal pathway in pressure-overload rats
1. The change of blood pressure: The tail arterial SBP in L-NAME group ratsincreased significantly with a time-dependent manner compared with that inmodel group rats, respectively (P<0.05or P<0.0l). Combined with MHBFC12mg/kg, the tail arterial SBP in the2nd,4th,6th weeks decreased significantlycompared with that in L-NAME group rats, respectively (P<0.05or P<0.0l).
2. The change of heart function: After6weeks of NO synthase inhibition, anenhanced contractility but a reduced diastolic compliance were taken place in L-NAME group rats (P＜0.01vs sham group), MHBFC could significantameliorate the LV function, and the ASBP and LVSP decreased significantly(P＜0.01vs L-NAME group).
3. Cardiac remodeling: At sixth week after aortic banding, the LVW/BW,RVW/BW and cardiomyocytes cross-section increased significantly in L-NAMEgroup rats (P＜0.05or P＜0.01vs sham group). The combination of MHBFC12mg/kg with L-NAME ameliorated cardiac hypertrophy significantly (P＜0.01vs L-NAME group). Histological examination demonstrated that both CVF,PVCA and myocardial tissue hydroxyproline increased significantly inL-NAME group compared with that in sham group rats (P＜0.01), and thecombination of MHBFC12mg/kg with L-NAME decreased cardiac tissuehydroxyproline significantly (P＜0.01vs L-NAME group).
4. The change of eNOS-NO: At sixth week after aortic banding, the eNOSprotein expression level was decreased significantly in mode group rats (P＜0.01vs sham group). Treatment with MHBFC12mg/kg, the eNOS proteinexpression level was increased significantly (P＜0.01vs model group). TheeNOS protein expression level was decreased significantly in L-NAME grouprats, but combination with MHBFC12mg/kg, the eNOS protein expressionlevel was increased significantly (P＜0.01vs L-NAME group). The plasma NOwas decreased significantly in L-NAME group rats, but combination withMHBFC12mg/kg, the plasma NO was increased significantly (P＜0.01vsL-NAME group).
Experiment3Studies of endothelial mechanisms of MHBFC base on thePGI2in pressure-overload rats
1. The change of blood pressure: At sixth week after aortic banding, the tailartery SBP and ASBP in Indo2group rats increased significantly with a time-dependent manner. Combination with MHBFC12mg/kg amelioratedindomethacin induced severe hemodynamics significantly (P＜0.05or P＜0.01vs Indo2group).
2. The change of heart function: At sixth week after aortic banding, the cardiaccontractility in Indo2group rats increased significantly, but a reduced cardiacdiastolic compliance significantly. Combined with MHBFC12mg/kg inhibitedthe increase of cardiac contractility, ameliorated cardiac compliance.
3. Cardiac remodeling: At sixth week after aortic banding, HW/BW, LVW/BW,RVW/BW and cardiomyocytes cross-section increased significantly in Indo2group (P＜0.01vs sham group). Combination with MHBFC12mg/kgameliorated cardiomyocytes hypertrophy significantly (P＜0.01vs Indo2group). Compared with sham group, the CVF, PVCA and hydroxyprolineincreased significantly in Indo2group (P＜0.01), and combination withMHBFC12mg/kg inhibited the deterioration of CVF and PVCA (P＜0.05or P＜0.01vs Indo2group), inhibited the increase of cardiac hydroxyproline (P＜0.01vs Indo2group).
4. The change of plasma PGI2content: At sixth week after aortic banding, theplasma PGI2content decreased significantly in model group rats (P＜0.01vssham group). Long-term treatment with MHBFC12mg/kg increased plasmaPGI2significantly (P＜0.01vs model group). Chronic administration of indodecreased plasma PGI2content significantly, and combination with MHBFC12mg/kg inhibited the decrease of plasma PGI2content significantly (P＜0.01vsIndo2group).
Conclusions:
1. MHBFC6,12mg/kg can significantly reverse pressure-overloadcardiovascular remodeling induced by abdominal aorta binding in rats with a certain extent of dose-dependent manner;
2. The protective mechanism of MHBFC on cardiovascular system inpressure-overload rats may be related to its regulation of endothelial function,augmenting NO and PGI2secretion, and inhibiting ET-1biosynthesis andsecretion, and ET-1system activation.
引文
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