过表达肌浆网钙ATP酶治疗慢性缺血性心力衰竭的实验研究
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摘要
第一章小型猪慢性缺血性心力衰竭模型的建立与评价
在我国,慢性心肌缺血已成为心力衰竭最重要的病因。本研究的目的是建立慢性缺血性心力衰竭的大动物模型,为研究其病理生理机制和防治手段奠定基础。采用开胸前降支起始段ameroid缩窄环植入法建立小型猪慢性缺血性心衰模型,术后第4周采用心肌核素灌注SPECT显像确认局部心肌缺血,经胸超声心动图检查测定心脏功能,并应用放射免疫法测定血清心衰相关炎性因子和神经体液因子的变化。缺血组12只小型猪顺利完成了开胸ameroid缩窄环植入术,4只动物行假手术作为对照。术后第4周缺血组前降支供血区域存在不可逆灌注缺损,与对照组相比,心脏整体收缩、舒张功能,缺血心肌局部厚度及局部运动能力均显著下降,伴随血清心衰相关炎性因子TNF-α,神经体液因子BNP、Ang II和ET-1水平的显著增高,符合慢性缺血性心衰的病理生理改变。说明在猪的前降支防治ameroid缩窄环是建立慢性缺血性心衰模型的可靠方法。
第二章SERCA2a过表达对慢性缺血性心力衰竭小型猪心功能的改善作用
转基因过表达SERCA2a可改善多种原因所致心衰动物模型的心功能,然而,其对慢性缺血性心衰心功能的影响还不清楚。本研究旨在观察重组腺相关病毒介导的SERCA2a基因转导对慢性缺血性心衰小心猪的治疗作用。将第一章建立的心衰动物模型,随机分为EGFP转导组和SERCA2a转导组,开胸心肌内直接注射进行基因转导。8周后超声心动图、血流动力学检测测定SERCA2a基因转导对心功能的影响,心肌核素灌注显像评价缺血区心肌灌注,放免法测定血清心衰相关炎性因子和神经体液因子,并行Western Blot测定缺血心肌中SERCA2a蛋白的表达量和活性变化。结果表明重组腺相关病毒可有效介导SERCA2a在心肌组织中的表达,8周后,与EGFP组相比,SERCA2a组心脏整体收缩、舒张功能,局部缺血心肌运动能力和缺血区室壁厚度均显著增加,伴随血清心衰相关炎性因子和神经体液因子水平的显著下降。两组缺血区心肌灌注情况无显著差异。表明SERCA2a过表达短期内(基因转导后8周)对缺血心肌灌注无影响,但可显著改善慢性缺血性心衰小型猪的心脏功能,可能成为慢性缺血性心衰治疗的潜在手段。
第三章SERCA2a过表达对慢性缺血心肌内质网应激-凋亡通路的影响
心肌细胞凋亡是缺血性心衰发生的重要原因,内质网应激-凋亡通路是新近发现的心肌细胞凋亡机制。本研究的目的是观察SERCA2a基因转导对缺血心肌细胞凋亡的影响及其与内质网应激-凋亡通路的关系。TUNEL法检测第二章各组动物缺血心肌细胞凋亡情况,行免疫组化和Western Blot测定UPR通路ATF6、IRE1和PERK的活化情况以及内质网应激相关凋亡通路CHOP、caspase-12和JNKs的活性。结果表明,缺血心肌组织中心肌细胞凋亡显著增强,伴随UPR信号通路、内质网应激相关凋亡通路及其下游信号分子的激活。SERCA2a基因转导可显著减轻缺血心肌细胞的凋亡,并可逆转上述UPR信号通路、内质网应激相关凋亡通路及其下游信号分子的活化。说明减弱内质网应激相关的缺血心肌细胞的凋亡,可能是SERCA2a基因转导治疗慢性缺血性心力衰竭的重要机制之一。
Chapter 1 Establishment and evaluation of chronic ischemic heart failure model in mini pig
Chronic myocardial ischemia has become the most important cause of heart failure in China. The aim of this study is to create a large animal model of chronic ischemic heart failure. Ameroid constrictor was implanted in the initial segment of LAD in mini pig by open chest surgery. Regional myocardial perfusion was assessed by SPECT. Cardiac function was determined by echocardiography and serum levels of heart failure related inflammatory factor TNF-α, neural-hormonal factors BNP, Ang II and ET-1 were also measured by radioimmunoassay. 4 weeks after ameroid implantation, a fixed perfusion defect was detected in LAD dependent area in ischemic pig. Also, the overall cardiac systolic and diastolic function, regional myocardial motion and thickness were significantly decreased compared with the control animal, with significant increase of the serum levels of the above heart failure related biomarkers. These results indicated that implantation of ameroid constrictor in the initial segment of LAD is a dependable way to create animal model of chronic ischemic heart failure.
Chapter 2 Improved cardiac function after SERCA2a gene delivery in mini pig model of chronic ischemic heart failure
SERCA2a gene delivery has been reported to be beneficial to the cardiac function in a variety of heart failure animal models, but its effects on chronic ischemic heart failure are still unknown. The aim of this study was to investigate whether SERCA2a gene delivery could improve the cardiac function in this heart failure type. Intramyocardial injection was performed to deliver the recombinant adeno-associated viral vector containing either EGFP or SERCA2a in chronic ischemic heart failure pigs. Effects of SERCA2a gene delivery on cardiac function were assessed by echocardiography and hemodynamic measurement. Changes of regional myocardial perfusion were determined by SPECT and changes of serum levels of heart failure related biomarkers were measured by radioimmunoassay. rAAV1-SERCA2a effectively restored the protein level and activity of SERCA2a in ischemic myocardium and significantly improved overall cardiac function 8 weeks after gene delivery, with significant decrease of serum heart failure related biomarkers. However, no improvement of regional myocardial perfusion was detected 8 weeks after SERCA2a gene delivery. These results demonstrated that intramyocardial rAAV1-SERCA2a gene delivery is an effective way to improve cardiac function of chronic ischemic heart failure in mini pig, indicating the potential therapeutic role of SERCA2a gene delivery in chronic ischemia induced heart failure.
Chapter 3 Attenuation of ER stress related myocardial apoptosis by SERCA2a gene delivery in a mini pig model chronic ischemic heart failure
Myocardial apoptosis has been reported to play an important role in the pathogenesis of chronic ischemic heart failure and ER stress-apoptosis signaling pathway is a newly defined mechanism of cellular apoptosis. The aim of this study is to investigate the effects of SERCA2a gene delivery in ischemic myocardial apoptosis and ER stress associated apoptosis pathway. TUNEL staining was used to measure the apoptosis of ischemic myocardium of animals in section 2. Immunohistochemistry and Western Blot were performed to detect the activation of the components of UPR pathway ATF6, IRE1 and PERK, and ER stress related apoptotic proteins CHOP, caspase-12 and JNKs. Enhanced myocardial apoptosis and activation of UPR pathway signaling proteins were detected in EGFP transduced animals compared to control, with significant increase of ER stress related apoptotic proteins, indicating ER stress related apoptosis was enhanced in the myocardium of chronic ischemic heart failure pigs. However, restoration of SERCA2a expression by gene transfer significantly attenuated the apoptosis of ischemic myocardium and reversed the activation of UPR pathway and ER stress related apoptotic proteins. These results demonstrated that the beneficial effects of SERCA2a gene delivery to chronic ischemic heart failure may be related to the attenuation of ER stress associated myocardial apoptosis.
在我国,慢性心肌缺血已成为心力衰竭最重要的病因。本研究的目的是建立慢性缺血性心力衰竭的大动物模型,为研究其病理生理机制和防治手段奠定基础。采用开胸前降支起始段ameroid缩窄环植入法建立小型猪慢性缺血性心衰模型,术后第4周采用心肌核素灌注SPECT显像确认局部心肌缺血,经胸超声心动图检查测定心脏功能,并应用放射免疫法测定血清心衰相关炎性因子和神经体液因子的变化。缺血组12只小型猪顺利完成了开胸ameroid缩窄环植入术,4只动物行假手术作为对照。术后第4周缺血组前降支供血区域存在不可逆灌注缺损,与对照组相比,心脏整体收缩、舒张功能,缺血心肌局部厚度及局部运动能力均显著下降,伴随血清心衰相关炎性因子TNF-α,神经体液因子BNP、Ang II和ET-1水平的显著增高,符合慢性缺血性心衰的病理生理改变。说明在猪的前降支防治ameroid缩窄环是建立慢性缺血性心衰模型的可靠方法。
第二章SERCA2a过表达对慢性缺血性心力衰竭小型猪心功能的改善作用
转基因过表达SERCA2a可改善多种原因所致心衰动物模型的心功能,然而,其对慢性缺血性心衰心功能的影响还不清楚。本研究旨在观察重组腺相关病毒介导的SERCA2a基因转导对慢性缺血性心衰小心猪的治疗作用。将第一章建立的心衰动物模型,随机分为EGFP转导组和SERCA2a转导组,开胸心肌内直接注射进行基因转导。8周后超声心动图、血流动力学检测测定SERCA2a基因转导对心功能的影响,心肌核素灌注显像评价缺血区心肌灌注,放免法测定血清心衰相关炎性因子和神经体液因子,并行Western Blot测定缺血心肌中SERCA2a蛋白的表达量和活性变化。结果表明重组腺相关病毒可有效介导SERCA2a在心肌组织中的表达,8周后,与EGFP组相比,SERCA2a组心脏整体收缩、舒张功能,局部缺血心肌运动能力和缺血区室壁厚度均显著增加,伴随血清心衰相关炎性因子和神经体液因子水平的显著下降。两组缺血区心肌灌注情况无显著差异。表明SERCA2a过表达短期内(基因转导后8周)对缺血心肌灌注无影响,但可显著改善慢性缺血性心衰小型猪的心脏功能,可能成为慢性缺血性心衰治疗的潜在手段。
第三章SERCA2a过表达对慢性缺血心肌内质网应激-凋亡通路的影响
心肌细胞凋亡是缺血性心衰发生的重要原因,内质网应激-凋亡通路是新近发现的心肌细胞凋亡机制。本研究的目的是观察SERCA2a基因转导对缺血心肌细胞凋亡的影响及其与内质网应激-凋亡通路的关系。TUNEL法检测第二章各组动物缺血心肌细胞凋亡情况,行免疫组化和Western Blot测定UPR通路ATF6、IRE1和PERK的活化情况以及内质网应激相关凋亡通路CHOP、caspase-12和JNKs的活性。结果表明,缺血心肌组织中心肌细胞凋亡显著增强,伴随UPR信号通路、内质网应激相关凋亡通路及其下游信号分子的激活。SERCA2a基因转导可显著减轻缺血心肌细胞的凋亡,并可逆转上述UPR信号通路、内质网应激相关凋亡通路及其下游信号分子的活化。说明减弱内质网应激相关的缺血心肌细胞的凋亡,可能是SERCA2a基因转导治疗慢性缺血性心力衰竭的重要机制之一。
Chapter 1 Establishment and evaluation of chronic ischemic heart failure model in mini pig
Chronic myocardial ischemia has become the most important cause of heart failure in China. The aim of this study is to create a large animal model of chronic ischemic heart failure. Ameroid constrictor was implanted in the initial segment of LAD in mini pig by open chest surgery. Regional myocardial perfusion was assessed by SPECT. Cardiac function was determined by echocardiography and serum levels of heart failure related inflammatory factor TNF-α, neural-hormonal factors BNP, Ang II and ET-1 were also measured by radioimmunoassay. 4 weeks after ameroid implantation, a fixed perfusion defect was detected in LAD dependent area in ischemic pig. Also, the overall cardiac systolic and diastolic function, regional myocardial motion and thickness were significantly decreased compared with the control animal, with significant increase of the serum levels of the above heart failure related biomarkers. These results indicated that implantation of ameroid constrictor in the initial segment of LAD is a dependable way to create animal model of chronic ischemic heart failure.
Chapter 2 Improved cardiac function after SERCA2a gene delivery in mini pig model of chronic ischemic heart failure
SERCA2a gene delivery has been reported to be beneficial to the cardiac function in a variety of heart failure animal models, but its effects on chronic ischemic heart failure are still unknown. The aim of this study was to investigate whether SERCA2a gene delivery could improve the cardiac function in this heart failure type. Intramyocardial injection was performed to deliver the recombinant adeno-associated viral vector containing either EGFP or SERCA2a in chronic ischemic heart failure pigs. Effects of SERCA2a gene delivery on cardiac function were assessed by echocardiography and hemodynamic measurement. Changes of regional myocardial perfusion were determined by SPECT and changes of serum levels of heart failure related biomarkers were measured by radioimmunoassay. rAAV1-SERCA2a effectively restored the protein level and activity of SERCA2a in ischemic myocardium and significantly improved overall cardiac function 8 weeks after gene delivery, with significant decrease of serum heart failure related biomarkers. However, no improvement of regional myocardial perfusion was detected 8 weeks after SERCA2a gene delivery. These results demonstrated that intramyocardial rAAV1-SERCA2a gene delivery is an effective way to improve cardiac function of chronic ischemic heart failure in mini pig, indicating the potential therapeutic role of SERCA2a gene delivery in chronic ischemia induced heart failure.
Chapter 3 Attenuation of ER stress related myocardial apoptosis by SERCA2a gene delivery in a mini pig model chronic ischemic heart failure
Myocardial apoptosis has been reported to play an important role in the pathogenesis of chronic ischemic heart failure and ER stress-apoptosis signaling pathway is a newly defined mechanism of cellular apoptosis. The aim of this study is to investigate the effects of SERCA2a gene delivery in ischemic myocardial apoptosis and ER stress associated apoptosis pathway. TUNEL staining was used to measure the apoptosis of ischemic myocardium of animals in section 2. Immunohistochemistry and Western Blot were performed to detect the activation of the components of UPR pathway ATF6, IRE1 and PERK, and ER stress related apoptotic proteins CHOP, caspase-12 and JNKs. Enhanced myocardial apoptosis and activation of UPR pathway signaling proteins were detected in EGFP transduced animals compared to control, with significant increase of ER stress related apoptotic proteins, indicating ER stress related apoptosis was enhanced in the myocardium of chronic ischemic heart failure pigs. However, restoration of SERCA2a expression by gene transfer significantly attenuated the apoptosis of ischemic myocardium and reversed the activation of UPR pathway and ER stress related apoptotic proteins. These results demonstrated that the beneficial effects of SERCA2a gene delivery to chronic ischemic heart failure may be related to the attenuation of ER stress associated myocardial apoptosis.
引文
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