舒张性心力衰竭的发病机制及药物干预研究
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摘要
第一部分:兔舒张性和收缩性心衰模型的建立及心室重构的比较
【研究目的】分别建立兔舒张性心衰和收缩性心衰的模型,并比较它们之间心功能和心室重构的差异。
【研究方法】新西兰白兔随机分为3组:假手术组、收缩性心衰组和舒张性心衰组(每组8只),采用腹主动脉缩窄术建立舒张性心衰模型,用主动脉瓣破瓣术建立收缩性心衰模型;使用心脏彩超和血流动力学检测心功能,用酶联免疫吸附法测定血清中B型脑钠肽、肾上腺素和去甲肾上腺素的含量;用HE染色和VG染色观察各组心肌组织的病理情况,用天狼猩红染色测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值,用羟脯氨酸法测定心肌胶原含量(CC)。
【研究结果】术后12周,与假手术组相比,舒张性心衰组左室壁明显增厚,心肌僵硬度增大,E/A比值明显增大,等容舒张期时间明显延长,心室舒张末压明显增大而射血分数正常,间质胶原含量、面积、容积分数及Ⅰ/Ⅲ型面积比值均显著升高(P均<0.01);收缩性心衰组左心室腔明显扩大,心室射血分数降低,心室舒张末压明显增大,间质胶原含量、面积及容积分数明显升高,但Ⅰ/Ⅲ型胶原面积比值下降(P<0.05或P<0.01)。此外,两心衰组的左房内径及血清中的B型脑钠肽、肾上腺素和去甲肾上腺素的含量均较假手术组显著升高(P<0.01)。
【结论】成功构建了兔舒张性心衰和收缩性心衰模型,收缩性心衰模型表现为左室腔明显扩大,室壁未见增厚;而舒张性心衰模型左室壁明显增厚,心腔未见扩大,且心肌间质重构较前者更为显著。
第二部分:兔舒张性和收缩性心衰模型之间钙渗漏特点的比较
【研究目的】比较兔舒张性心衰和收缩性心衰模型之间钙渗漏特点以及相关调节蛋白表达和活性的差异并探讨其可能的机制。
【研究方法】用钙离子荧光成像仪进行肌浆网钙渗漏的检测,采用分子生物学技术(RT-PCR和Western blot)检测各组心肌组织中FK506结合蛋白12.6(FKBP12.6)、Ca~(2+)/钙调素依赖的蛋白激酶Ⅱ(CaMKⅡ)、蛋白激酶A(PKA)、兰尼碱受体(RyR2)及其磷酸化位点表达和磷酸化状态,利用γ-32P底物掺入法测定CaMKⅡ、PKA的活性。
【研究结果】与假手术组相比,在舒张性心衰组中没有检测到明显的肌浆网钙渗漏,FKBP12.6在心肌中的表达总量显著下降(P<0.05),PKA的表达和活性均明显升高(P<0.05或P<0.01),以及该酶在RyR2的磷酸化位点(RyR2-P2809)的磷酸化状态也显著增高(P<0.05),而CaMKⅡ的表达和活性及其在RyR2的磷酸化位点(RyR2-P2815)的磷酸化状态则无明显改变;在收缩性心衰组中检测出异常增高的钙渗漏(P<0.01),FKBP12.6在心肌中的总表达量及其与RyR2的结合量均显著下降(P<0.05),PKA和CaMKⅡ的表达和活性及其它们在RyR2的磷酸化位点的磷酸化状态均显著升高(P<0.05或P<0.01)。
【结论】在收缩性心衰模型中发现了异常增高的钙渗漏,而在舒张性心衰模型中并未检测到类似的现象,这可能是舒张性心衰保留有正常的心室收缩功能的原因之一,CaMKⅡ在肌浆网钙渗漏中可能起着更为关键的作用。
第三部分:兔舒张性和收缩性心衰模型之间钙回摄功能的比较
【研究目的】比较兔舒张性心衰和收缩性心衰模型之间钙回摄功能及其钙调节相关蛋白的表达和活性的差异并探讨其可能的机制。
【研究方法】用钙离子荧光成像仪进行肌浆网钙回摄功能的检测,采用分子生物学技术(RT-PCR和Western blot)检测各组心肌组织中肌浆网钙泵(SERCA2a)、受磷蛋白(PLB)、Ca~(2+)/钙调素依赖的蛋白激酶Ⅱ(CaMKⅡ)、蛋白激酶A(PKA)和蛋白磷脂酶(PP1α)等蛋白的表达,利用γ-32P底物掺入法测定CaMKⅡ、PKA的活性。
【研究结果】与假手术组相比,舒张性心衰组和收缩性心衰组中钙回摄量均显著下降(P<0.01),SERCA2a在心肌中的表达量和活性也均显著下降(P<0.05),且PKA的表达和活性均明显升高(P<0.05或P<0.01),PP1α的表达量也显著升高(P<0.05)。在舒张性心衰组中NCX、PLB及其磷酸化位点(Ser-16)的表达水平和磷酸化状态无明显改变;而在收缩性心衰组中PLB及其磷酸化位点(Ser-16)的表达水平和磷酸化状态也明显降低(P<0.05),但NCX的蛋白表达水平却明显升高(P<0.05)。
【结论】舒张性心衰和收缩性心衰模型中肌浆网钙回摄功能、SERCA2a的表达和活性均显著下降,收缩性心衰模型中NCX的表达明显升高;舒张性心衰模型中NCX的表达无明显改变,这可能是两种心衰发病机制不同的原因之一。
第四部分:阿托伐他汀对兔舒张性心衰模型心室重构及钙调节相关蛋白表达的影响
【研究目的】研究阿托伐他汀对舒张性心衰心室重构及钙调节相关蛋白表达的影响。【研究方法】新西兰白兔随机分为3组:假手术组、舒张性心衰组和阿托伐他汀组(每组8只),采用腹主动脉缩窄术建立舒张性心衰模型,阿托伐他汀组腹主动脉缩窄术后24h给予阿托伐他汀5mg.kg~(-1).d~(-1),通过心脏超声和血流动力学检查比较三者心功能的差异,通过HE染色和VG染色观察各组心肌组织的病理情况的差异,通过心肌胶原含量(CC)测定(羟脯氨酸法)和天狼猩红染色(PSR)测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值比较三者间质重构的差异。通过Western blot比较各组心肌组织中肌浆网钙泵(SERCA2a)、蛋白激酶A(PKA)和蛋白磷脂酶(PP1α)表达的差异。
【研究结果】术后12周,与假手术组相比,舒张性心衰组心超检查发现室间隔和左室后壁明显增厚,左房内径明显扩大,E/A比值明显升高、等容舒张期时间显著延长(P均<0.01),而射血分数正常;血流动力学左室舒张末压力明显升高,左室松弛时间常数(tau)也显著延长(P<0.01);间质胶原含量、总面积、容积分数及Ⅰ/Ⅲ型面积比值均显著升高(P<0.01),心肌组织中SERCA2a蛋白表达明显下降,PKA和PP1α蛋白表达则明显升高(P<0.05)。阿托伐他汀组的室间隔、左室后壁、间质胶原含量、总面积和容积分数均明显低于舒张性心衰组,但略高于假手术组(P<0.05或P<0.01),而上述其余指标与假手术组比无明显改变。
【结论】:阿托伐他汀可以显著改善压力负荷导致的心室重构并能调节其钙调节相关蛋白的表达,从而延缓整个病理过程发展到舒张性心衰。
第五部分:替米沙坦对兔舒张性心衰模型心室重构及钙调节相关蛋白表达的影响
【研究目的】探讨替米沙坦对舒张性心衰的心室重构及钙调节相关蛋白表达的影响。
【研究方法】新西兰白兔随机分为3组:假手术组、舒张性心衰组和替米沙坦组(每组各8只),舒张性心衰组采用腹主动脉缩窄术,替米沙坦组于腹主动脉缩窄术后给予替米沙坦10mg.kg~(-1).d~(-1),通过心脏超声和血流动力学检测比较三者心功能的差异,通过HE染色和VG染色比较各组心肌组织的病理情况的差异,通过心肌胶原含量(CC)测定(羟脯氨酸法)和天狼猩红染色测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值比较三者间质重构的差异,通过Western blot比较各组心肌组织中SERCA2a、PKA和PP1α表达的差异。
【研究结果】术后12周左右,舒张性心衰组与假手术组相比,心超显示左室后壁和室间隔明显增厚,左房内径显著增大,E/A比值明显升高、等容舒张期时间显著延长(P均<0.01),但射血分数正常;血流动力学显示左室舒张末压力明显升高,左室松弛时间常数也显著延长(P<0.01);间质胶原总面积、胶原含量、容积分数及Ⅰ/Ⅲ型胶原面积比值均显著升高(P均<0.01),心肌组织中SERCA2a蛋白表达显著下降,PKA和PP1α蛋白表达则明显升高(P均<0.05)。而替米沙坦组的室间隔厚度、左室后壁厚度、间质胶原总面积、胶原含量和容积分数均明显低于舒张性心衰组,但又略高于假手术组(P<0.05或P<0.01),而上述其余指标与假手术组相比则无明显改变。
【结论】:替米沙坦可以显著改善压力负荷诱导的心室重构并能调节其钙调节相关蛋白的表达,从而延缓整个病理过程发展到舒张性心衰。
PartⅠ: Establishment and comparison in rabbit models with diastolic heart failure and systolic heart failure
Objective: To establish the diastolic heart failure (DHF) and systolic heart failure (SHF) rabbit models respectively, and to compare the differences in cardiac function and ventricular remodeling between them.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and SHF group. The DHF model was established by abdomial aorta constriction, and the SHF model was established by aortic insufficiency. Cardiac function was measured by echocardiography and hemodynamic assays. The BNP (B-type brain natriuretic peptide), NE (norepinephrine), and EPI (epinephrine) were measured by Enzyme-Linked Immunosorbent Assays (ELISA). The pathological stutas was observed by HE stain and VG stain. The collagen content (CC) was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain.
Results: After surgery 12 weeks, compared with the SO group, there was significantly increased ventricular wall thickness and stiffness, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increasing CC, CA, CVF and area ratio ofⅠtoⅢtype collagen in DHF group(P<0.01); there were significantly enlarged left ventricular chamber, decreased LVEF, increased LVEDP, and significantly increasing collagen content, CA, CVF but decreased ratio ofⅠtoⅢtype collagen in SHF group(P<0.05 or P<0.01). Moreover, there were increased LAd, BNP, NE and EPI in both of DHF and SHF groups (P<0.01).
Conclution: The DHF and SHF rabbit models were established successfully, there was enlarged left ventricular chamber and unchanged ventricular wall thickness in the SHF model; whereas there was increased ventricular wall thickness and unchanged ventricular chamber in the DHF model, and more severe interstitial remodeling than that in the former.
PartⅡ: The differences in sarcoplasmic reticulum Ca~(2+) leak characters between systolic and diastolic heart failure rabbit models
Objective: To compare the differences in Ca~(2+) leak characters and the expression and activities of the related proteins, and to investigate the potential mechanisms.
Methods: The SR Ca~(2+) leak was measured with a calcium imaging device. The expression of FK-506 binding protein 12.6 (FKBP12.6), Ca~(2+)/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), ryanodine receptor (RyR2) and its phosphorylation sites were evaluated by RT-PCR and Western blots. The activities of PKA and CaMKⅡwere detected byγ-32P substrate incorporation.
Results: Compared with the SO group, in the DHF group, there was reduced total amount of FKBP12.6 (P<0.05), increased expression and activity of PKA (P<0.05 or P<0.01) and its phosphorylation site RyR2-P2809 in the RyR2 (P<0.05), but no prominent Ca~(2+) leak; whereas in the SHF group, there was significantly enhanced SR Ca~(2+) leak (P<0.01), reduced total amount of FKBP12.6 and association amount of FKBP12.6-RyR2 (P<0.05), increased expression and activity of PKA and CaMKII and their phosphorylation status in the RyR2-P2809 and RyR2-P2815 (P<0.05 or P<0.01).
Conclution: In the SHF group, there was abnormal enhanced SR Ca~(2+) leak, but the prominent SR Ca~(2+) leak is not observed in DHF model, which may be one of the reasons in preserved systolic function, and CaMKII possibly plays more important role in SR Ca~(2+) leak.
PartⅢ: The differences in sarcoplasmic reticulum Ca~(2+) re-uptake function between systolic and diastolic heart failure rabbit models
Objective: To compare the differences in calcium re-uptake function and the expression and activities of the calcium regulation related proteins, and to investigate the potential mechanisms.
Methods: The SR Ca~(2+) re-uptake function was measured with a calcium imaging device. The expression of sarcoplasmic reticulum calcium adenodine triphosphatase2a (SERCA2a), CaMKII, PKA, PP1α, phospholamban (PLB) and its phosphorylation site (Ser-16) were evaluated by RT-PCR and Western blots. The activities of PKA and CaMKⅡwere detected byγ-32P substrate incorporation.
Results: Compared with the SO group, there was reduced Ca~(2+) re-uptake amount (P<0.01) and the expression and activity of SERCA2a (P<0.05 or P<0.01), increased the expression and activity of PKA and PP1αin both of DHF and SHF groups (P<0.05 or P<0.01). In the DHF group, there was unchanged the expression of NCX, PLB and its phosphorylation site (Ser-16); whereas in the SHF group, there was reduced expression of PLB and its phosphorylation site Ser-16 (P<0.05), but significantly increased expression of NCX (P<0.05).
Conclution: There was reduced Ca~(2+) re-uptake function, reduced expression and activities of SERCA2a in both of DHF and SHF groups, and there was increased expression of NCX in the SHF group, whereas there were unchanged expression of NCX in the DHF group, which may be one of the reasons in different pathogenesis between the two HF models.
PartⅣ: The effect of Atorvastatin on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model
Objective: To investigate the effect of atorvastatin on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and atorvastatin group. The DHF model was established by abdomial aorta constriction, and the atorvastatin model was supplied as 5mg.kg-1.d-1 after the operation of abdomial aorta constriction 24 hours. Cardiac function was measured by echocardiography and hemodynamic assays. The pathological stutas was observed by HE stain and VG stain. The collagen content (CC) was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain. The expression of SERCA2a, PKA and PP1αwere evaluated by Western blots.
Results: After surgery 12 weeks, compared with the SO group, there was significantly increased IVSd, LVPWd and LAd, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increased CC, CA, CVF and area ratio ofⅠtoⅢtype collagen (P<0.01), reduced the expression of SERCA2a (P<0.05), increased the expression of PKA and PP1α(P<0.05) in the DHF group. And IVSd, LVPWd, CC, CA, CVF in atorvastatin group were lower than those in the DHF group(P<0.01), but little higher than those in the SO group(P<0.05 or P<0.01), and the other data above-mentioned were unchanged in atorvastatin group. Conclution: Atorvastatin can significantly improve the pressure overload induced ventricular remodeling and regulate the expression of calcium regulatory proteins, thus it can postpone the whole pathological progression develop to DHF.
PartⅤ: The effect of Telmisartan on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model
Objective: To investigate the effect of telmisartan on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and telmisartan group. The DHF model was established by abdomial aorta constriction, and the telmisartan model was supplied as 10mg.kg~(-1).d~(-1) after the operation of abdomial aorta constriction 24 hours. Cardiac function was measured by echocardiography and hemodynamic assays. The pathological stutas was observed by HE stain and VG stain. The collagen content was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain. The expression of SERCA2a, PKA and PP1αwere evaluated by Western blots.
Results: After about surgery 12 weeks, compared with SO group, there was significantly increased IVSd, LVPWd and LAd, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increased CA, CC, CVF and area ratio ofⅠtoⅠtype collagen (P<0.01), reduced the expression of SERCA2a (P<0.05), increased the expression of PKA and PP1α(P<0.05) in the DHF group. And IVSd, LVPWd, CC, CA, CVF in telmisartan group were lower than those in the DHF group(P<0.01), but little higher than those in the SO group(P<0.05 or P<0.01), and the other data above-mentioned were unchanged in telmisartan group.
Conclution: Telmisartan can significantly improve the pressure overload induced ventricular remodeling and regulate the expression of calcium regulatory proteins, thus it can postpone the whole pathological progression develop to DHF.
【研究目的】分别建立兔舒张性心衰和收缩性心衰的模型,并比较它们之间心功能和心室重构的差异。
【研究方法】新西兰白兔随机分为3组:假手术组、收缩性心衰组和舒张性心衰组(每组8只),采用腹主动脉缩窄术建立舒张性心衰模型,用主动脉瓣破瓣术建立收缩性心衰模型;使用心脏彩超和血流动力学检测心功能,用酶联免疫吸附法测定血清中B型脑钠肽、肾上腺素和去甲肾上腺素的含量;用HE染色和VG染色观察各组心肌组织的病理情况,用天狼猩红染色测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值,用羟脯氨酸法测定心肌胶原含量(CC)。
【研究结果】术后12周,与假手术组相比,舒张性心衰组左室壁明显增厚,心肌僵硬度增大,E/A比值明显增大,等容舒张期时间明显延长,心室舒张末压明显增大而射血分数正常,间质胶原含量、面积、容积分数及Ⅰ/Ⅲ型面积比值均显著升高(P均<0.01);收缩性心衰组左心室腔明显扩大,心室射血分数降低,心室舒张末压明显增大,间质胶原含量、面积及容积分数明显升高,但Ⅰ/Ⅲ型胶原面积比值下降(P<0.05或P<0.01)。此外,两心衰组的左房内径及血清中的B型脑钠肽、肾上腺素和去甲肾上腺素的含量均较假手术组显著升高(P<0.01)。
【结论】成功构建了兔舒张性心衰和收缩性心衰模型,收缩性心衰模型表现为左室腔明显扩大,室壁未见增厚;而舒张性心衰模型左室壁明显增厚,心腔未见扩大,且心肌间质重构较前者更为显著。
第二部分:兔舒张性和收缩性心衰模型之间钙渗漏特点的比较
【研究目的】比较兔舒张性心衰和收缩性心衰模型之间钙渗漏特点以及相关调节蛋白表达和活性的差异并探讨其可能的机制。
【研究方法】用钙离子荧光成像仪进行肌浆网钙渗漏的检测,采用分子生物学技术(RT-PCR和Western blot)检测各组心肌组织中FK506结合蛋白12.6(FKBP12.6)、Ca~(2+)/钙调素依赖的蛋白激酶Ⅱ(CaMKⅡ)、蛋白激酶A(PKA)、兰尼碱受体(RyR2)及其磷酸化位点表达和磷酸化状态,利用γ-32P底物掺入法测定CaMKⅡ、PKA的活性。
【研究结果】与假手术组相比,在舒张性心衰组中没有检测到明显的肌浆网钙渗漏,FKBP12.6在心肌中的表达总量显著下降(P<0.05),PKA的表达和活性均明显升高(P<0.05或P<0.01),以及该酶在RyR2的磷酸化位点(RyR2-P2809)的磷酸化状态也显著增高(P<0.05),而CaMKⅡ的表达和活性及其在RyR2的磷酸化位点(RyR2-P2815)的磷酸化状态则无明显改变;在收缩性心衰组中检测出异常增高的钙渗漏(P<0.01),FKBP12.6在心肌中的总表达量及其与RyR2的结合量均显著下降(P<0.05),PKA和CaMKⅡ的表达和活性及其它们在RyR2的磷酸化位点的磷酸化状态均显著升高(P<0.05或P<0.01)。
【结论】在收缩性心衰模型中发现了异常增高的钙渗漏,而在舒张性心衰模型中并未检测到类似的现象,这可能是舒张性心衰保留有正常的心室收缩功能的原因之一,CaMKⅡ在肌浆网钙渗漏中可能起着更为关键的作用。
第三部分:兔舒张性和收缩性心衰模型之间钙回摄功能的比较
【研究目的】比较兔舒张性心衰和收缩性心衰模型之间钙回摄功能及其钙调节相关蛋白的表达和活性的差异并探讨其可能的机制。
【研究方法】用钙离子荧光成像仪进行肌浆网钙回摄功能的检测,采用分子生物学技术(RT-PCR和Western blot)检测各组心肌组织中肌浆网钙泵(SERCA2a)、受磷蛋白(PLB)、Ca~(2+)/钙调素依赖的蛋白激酶Ⅱ(CaMKⅡ)、蛋白激酶A(PKA)和蛋白磷脂酶(PP1α)等蛋白的表达,利用γ-32P底物掺入法测定CaMKⅡ、PKA的活性。
【研究结果】与假手术组相比,舒张性心衰组和收缩性心衰组中钙回摄量均显著下降(P<0.01),SERCA2a在心肌中的表达量和活性也均显著下降(P<0.05),且PKA的表达和活性均明显升高(P<0.05或P<0.01),PP1α的表达量也显著升高(P<0.05)。在舒张性心衰组中NCX、PLB及其磷酸化位点(Ser-16)的表达水平和磷酸化状态无明显改变;而在收缩性心衰组中PLB及其磷酸化位点(Ser-16)的表达水平和磷酸化状态也明显降低(P<0.05),但NCX的蛋白表达水平却明显升高(P<0.05)。
【结论】舒张性心衰和收缩性心衰模型中肌浆网钙回摄功能、SERCA2a的表达和活性均显著下降,收缩性心衰模型中NCX的表达明显升高;舒张性心衰模型中NCX的表达无明显改变,这可能是两种心衰发病机制不同的原因之一。
第四部分:阿托伐他汀对兔舒张性心衰模型心室重构及钙调节相关蛋白表达的影响
【研究目的】研究阿托伐他汀对舒张性心衰心室重构及钙调节相关蛋白表达的影响。【研究方法】新西兰白兔随机分为3组:假手术组、舒张性心衰组和阿托伐他汀组(每组8只),采用腹主动脉缩窄术建立舒张性心衰模型,阿托伐他汀组腹主动脉缩窄术后24h给予阿托伐他汀5mg.kg~(-1).d~(-1),通过心脏超声和血流动力学检查比较三者心功能的差异,通过HE染色和VG染色观察各组心肌组织的病理情况的差异,通过心肌胶原含量(CC)测定(羟脯氨酸法)和天狼猩红染色(PSR)测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值比较三者间质重构的差异。通过Western blot比较各组心肌组织中肌浆网钙泵(SERCA2a)、蛋白激酶A(PKA)和蛋白磷脂酶(PP1α)表达的差异。
【研究结果】术后12周,与假手术组相比,舒张性心衰组心超检查发现室间隔和左室后壁明显增厚,左房内径明显扩大,E/A比值明显升高、等容舒张期时间显著延长(P均<0.01),而射血分数正常;血流动力学左室舒张末压力明显升高,左室松弛时间常数(tau)也显著延长(P<0.01);间质胶原含量、总面积、容积分数及Ⅰ/Ⅲ型面积比值均显著升高(P<0.01),心肌组织中SERCA2a蛋白表达明显下降,PKA和PP1α蛋白表达则明显升高(P<0.05)。阿托伐他汀组的室间隔、左室后壁、间质胶原含量、总面积和容积分数均明显低于舒张性心衰组,但略高于假手术组(P<0.05或P<0.01),而上述其余指标与假手术组比无明显改变。
【结论】:阿托伐他汀可以显著改善压力负荷导致的心室重构并能调节其钙调节相关蛋白的表达,从而延缓整个病理过程发展到舒张性心衰。
第五部分:替米沙坦对兔舒张性心衰模型心室重构及钙调节相关蛋白表达的影响
【研究目的】探讨替米沙坦对舒张性心衰的心室重构及钙调节相关蛋白表达的影响。
【研究方法】新西兰白兔随机分为3组:假手术组、舒张性心衰组和替米沙坦组(每组各8只),舒张性心衰组采用腹主动脉缩窄术,替米沙坦组于腹主动脉缩窄术后给予替米沙坦10mg.kg~(-1).d~(-1),通过心脏超声和血流动力学检测比较三者心功能的差异,通过HE染色和VG染色比较各组心肌组织的病理情况的差异,通过心肌胶原含量(CC)测定(羟脯氨酸法)和天狼猩红染色测定胶原面积(CA)、容积分数(CVF)及Ⅰ/Ⅲ型胶原的面积比值比较三者间质重构的差异,通过Western blot比较各组心肌组织中SERCA2a、PKA和PP1α表达的差异。
【研究结果】术后12周左右,舒张性心衰组与假手术组相比,心超显示左室后壁和室间隔明显增厚,左房内径显著增大,E/A比值明显升高、等容舒张期时间显著延长(P均<0.01),但射血分数正常;血流动力学显示左室舒张末压力明显升高,左室松弛时间常数也显著延长(P<0.01);间质胶原总面积、胶原含量、容积分数及Ⅰ/Ⅲ型胶原面积比值均显著升高(P均<0.01),心肌组织中SERCA2a蛋白表达显著下降,PKA和PP1α蛋白表达则明显升高(P均<0.05)。而替米沙坦组的室间隔厚度、左室后壁厚度、间质胶原总面积、胶原含量和容积分数均明显低于舒张性心衰组,但又略高于假手术组(P<0.05或P<0.01),而上述其余指标与假手术组相比则无明显改变。
【结论】:替米沙坦可以显著改善压力负荷诱导的心室重构并能调节其钙调节相关蛋白的表达,从而延缓整个病理过程发展到舒张性心衰。
PartⅠ: Establishment and comparison in rabbit models with diastolic heart failure and systolic heart failure
Objective: To establish the diastolic heart failure (DHF) and systolic heart failure (SHF) rabbit models respectively, and to compare the differences in cardiac function and ventricular remodeling between them.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and SHF group. The DHF model was established by abdomial aorta constriction, and the SHF model was established by aortic insufficiency. Cardiac function was measured by echocardiography and hemodynamic assays. The BNP (B-type brain natriuretic peptide), NE (norepinephrine), and EPI (epinephrine) were measured by Enzyme-Linked Immunosorbent Assays (ELISA). The pathological stutas was observed by HE stain and VG stain. The collagen content (CC) was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain.
Results: After surgery 12 weeks, compared with the SO group, there was significantly increased ventricular wall thickness and stiffness, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increasing CC, CA, CVF and area ratio ofⅠtoⅢtype collagen in DHF group(P<0.01); there were significantly enlarged left ventricular chamber, decreased LVEF, increased LVEDP, and significantly increasing collagen content, CA, CVF but decreased ratio ofⅠtoⅢtype collagen in SHF group(P<0.05 or P<0.01). Moreover, there were increased LAd, BNP, NE and EPI in both of DHF and SHF groups (P<0.01).
Conclution: The DHF and SHF rabbit models were established successfully, there was enlarged left ventricular chamber and unchanged ventricular wall thickness in the SHF model; whereas there was increased ventricular wall thickness and unchanged ventricular chamber in the DHF model, and more severe interstitial remodeling than that in the former.
PartⅡ: The differences in sarcoplasmic reticulum Ca~(2+) leak characters between systolic and diastolic heart failure rabbit models
Objective: To compare the differences in Ca~(2+) leak characters and the expression and activities of the related proteins, and to investigate the potential mechanisms.
Methods: The SR Ca~(2+) leak was measured with a calcium imaging device. The expression of FK-506 binding protein 12.6 (FKBP12.6), Ca~(2+)/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), ryanodine receptor (RyR2) and its phosphorylation sites were evaluated by RT-PCR and Western blots. The activities of PKA and CaMKⅡwere detected byγ-32P substrate incorporation.
Results: Compared with the SO group, in the DHF group, there was reduced total amount of FKBP12.6 (P<0.05), increased expression and activity of PKA (P<0.05 or P<0.01) and its phosphorylation site RyR2-P2809 in the RyR2 (P<0.05), but no prominent Ca~(2+) leak; whereas in the SHF group, there was significantly enhanced SR Ca~(2+) leak (P<0.01), reduced total amount of FKBP12.6 and association amount of FKBP12.6-RyR2 (P<0.05), increased expression and activity of PKA and CaMKII and their phosphorylation status in the RyR2-P2809 and RyR2-P2815 (P<0.05 or P<0.01).
Conclution: In the SHF group, there was abnormal enhanced SR Ca~(2+) leak, but the prominent SR Ca~(2+) leak is not observed in DHF model, which may be one of the reasons in preserved systolic function, and CaMKII possibly plays more important role in SR Ca~(2+) leak.
PartⅢ: The differences in sarcoplasmic reticulum Ca~(2+) re-uptake function between systolic and diastolic heart failure rabbit models
Objective: To compare the differences in calcium re-uptake function and the expression and activities of the calcium regulation related proteins, and to investigate the potential mechanisms.
Methods: The SR Ca~(2+) re-uptake function was measured with a calcium imaging device. The expression of sarcoplasmic reticulum calcium adenodine triphosphatase2a (SERCA2a), CaMKII, PKA, PP1α, phospholamban (PLB) and its phosphorylation site (Ser-16) were evaluated by RT-PCR and Western blots. The activities of PKA and CaMKⅡwere detected byγ-32P substrate incorporation.
Results: Compared with the SO group, there was reduced Ca~(2+) re-uptake amount (P<0.01) and the expression and activity of SERCA2a (P<0.05 or P<0.01), increased the expression and activity of PKA and PP1αin both of DHF and SHF groups (P<0.05 or P<0.01). In the DHF group, there was unchanged the expression of NCX, PLB and its phosphorylation site (Ser-16); whereas in the SHF group, there was reduced expression of PLB and its phosphorylation site Ser-16 (P<0.05), but significantly increased expression of NCX (P<0.05).
Conclution: There was reduced Ca~(2+) re-uptake function, reduced expression and activities of SERCA2a in both of DHF and SHF groups, and there was increased expression of NCX in the SHF group, whereas there were unchanged expression of NCX in the DHF group, which may be one of the reasons in different pathogenesis between the two HF models.
PartⅣ: The effect of Atorvastatin on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model
Objective: To investigate the effect of atorvastatin on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and atorvastatin group. The DHF model was established by abdomial aorta constriction, and the atorvastatin model was supplied as 5mg.kg-1.d-1 after the operation of abdomial aorta constriction 24 hours. Cardiac function was measured by echocardiography and hemodynamic assays. The pathological stutas was observed by HE stain and VG stain. The collagen content (CC) was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain. The expression of SERCA2a, PKA and PP1αwere evaluated by Western blots.
Results: After surgery 12 weeks, compared with the SO group, there was significantly increased IVSd, LVPWd and LAd, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increased CC, CA, CVF and area ratio ofⅠtoⅢtype collagen (P<0.01), reduced the expression of SERCA2a (P<0.05), increased the expression of PKA and PP1α(P<0.05) in the DHF group. And IVSd, LVPWd, CC, CA, CVF in atorvastatin group were lower than those in the DHF group(P<0.01), but little higher than those in the SO group(P<0.05 or P<0.01), and the other data above-mentioned were unchanged in atorvastatin group. Conclution: Atorvastatin can significantly improve the pressure overload induced ventricular remodeling and regulate the expression of calcium regulatory proteins, thus it can postpone the whole pathological progression develop to DHF.
PartⅤ: The effect of Telmisartan on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model
Objective: To investigate the effect of telmisartan on ventricular remodeling and expression of calcium regulatory proteins in the diastolic heart failure rabbit model.
Methods: New Zealand white rabbits were randomly divided into three groups (n=8 in each group): sham operation (SO) group, DHF group, and telmisartan group. The DHF model was established by abdomial aorta constriction, and the telmisartan model was supplied as 10mg.kg~(-1).d~(-1) after the operation of abdomial aorta constriction 24 hours. Cardiac function was measured by echocardiography and hemodynamic assays. The pathological stutas was observed by HE stain and VG stain. The collagen content was detected through hydroxyproline colorimetric assay and collagen area (CA), collagen volume fraction(CVF) and area ratio ofⅠtoⅢtype collagen were detected by PSR stain. The expression of SERCA2a, PKA and PP1αwere evaluated by Western blots.
Results: After about surgery 12 weeks, compared with SO group, there was significantly increased IVSd, LVPWd and LAd, increased E/A and LVEDP, prolonged IVRT and tau (P<0.01), but normal left ventricular ejection fraction (LVEF), and significantly increased CA, CC, CVF and area ratio ofⅠtoⅠtype collagen (P<0.01), reduced the expression of SERCA2a (P<0.05), increased the expression of PKA and PP1α(P<0.05) in the DHF group. And IVSd, LVPWd, CC, CA, CVF in telmisartan group were lower than those in the DHF group(P<0.01), but little higher than those in the SO group(P<0.05 or P<0.01), and the other data above-mentioned were unchanged in telmisartan group.
Conclution: Telmisartan can significantly improve the pressure overload induced ventricular remodeling and regulate the expression of calcium regulatory proteins, thus it can postpone the whole pathological progression develop to DHF.
引文
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