摘要
目的：
本研究旨在观察不同年龄小鼠急性心肌梗塞后心脏破裂心室重构及核因子NF-κB表达的差异,并进一步以携带抗NF-κB核酶基因的重组9型腺相关病毒(rAAV9),靶向抑制老龄小鼠心肌NF-κB信号转导通路,探讨老龄小鼠急性心梗后心脏破裂心室重构的分子机制。本研究包括：1)建立小鼠急性心肌梗塞模型,研究不同年龄小鼠急性心梗后心脏破裂和心室重构及NF-κB活性、p65、p50,细胞间粘附分子(ICAM)-1和血管细胞粘附分子(VCAM)-1表达的差异。2)探讨重组9型腺相关病毒载体对小鼠心脏的转染效果及对心功能的影响。3)研究应用携带抗NF-κB核酶基因的重组9型腺相关病毒,靶向抑制心肌NF-κB信号转导通路,是否可以减轻老龄小鼠急性心梗后心脏破裂及心室重构。
方法：
课题第一部分：1)近交系C57BL/6低龄(3月龄Young, Y)和老龄(18月龄Old,O)小鼠各80只,共160只,开胸结扎左冠状动脉,建立小鼠急性心肌梗塞模型,随机分为假手术组(sham operation, SH)10只,心梗组(myocardial infarction,MI)70只,观察小鼠心脏破裂发生,心肌梗死面积,左心室重构情况,进行不同年龄组的对比研究。2)另选低龄和老龄小鼠各48只,共96只,根据心梗时间分为SH、心梗(MI)3天、7天、14天组,根据分组在心梗后不同时间处死小鼠留取心脏标本,液氮冻存或甲醛固定备用。应用免疫组化法测定不同年龄小鼠心肌梗塞后p65、p50表达,并进行对比。Western Blot法测定不同年龄小鼠心肌梗塞后p65、p50,粘附分子ICAM-1、VCAM-1表达。
课题第二部分：1)16只C57BL/6小鼠经尾静脉将携带增强型绿色荧光蛋白(enhanced green fluorescent protein, eGFP)报告基因的rAAV9 (rAAV9-eGFP)转染入小鼠,于7d、14d、21d、28d留取标本,使用荧光显微镜观察eGFP在心肌、肝、肺、肾、脑、骨骼肌的荧光表达,Western Blot法检测eGFP的蛋白表达。2)20只C57BL/6小鼠随机分为2组,每组10只,分别经尾静脉注射rAAV9-eGFP和生理盐水,28d后行心脏超声及血流动力学检查。
课题第三部分：1)160只老龄(18月龄)C57BL/6小鼠建立急性心肌梗塞模型,随机分组,75只术前16天经尾静脉给予重组腺相关病毒rAAV9-R65注射,为R65+MI组,75只为MI组。其余10只为假手术(SH)组。术后7天进行心脏彩超检查了解左室重构情况,并检测心肌梗死面积,心脏破裂率,死亡率。2)EMSA法检测NF-кB活性,酶谱法检测基质金属蛋白酶(matrixmetalloproteinases, MMP)-2,9活性,Western Blot法检测p65、肿瘤坏死因子(TNF)-α、IL-Iβ、粘附分子ICAM-1、VCAM-1表达,天狼猩红染色检测胶原含量。
结果：
课题第一部分：1)两组梗死面积比较无统计学差异,老龄组小鼠心梗后1周心脏破裂的发生率显著升高(33.9% vs 15.6%,P=0.017)。与假手术组相比,MI各组均出现明显的左室扩张和心功能障碍。与低龄MI组相比,老龄MI组心梗7天时出现明显的梗死区变薄扩张和收缩功能障碍,表现为LVEDd、LVESd、EXLVDd明显增加,Pws、Pwd和FS值明显降低(P<0.05)。血液动力学测定：老龄假手术组与低龄假手术组比较,-dp/dtmax明显增高(P<0.05)；老龄MI组与低龄MI组相比,SBP、DBP、LVSP增高(P<0.05)。MI组与假手术组相比,各组SBP、DBP、LVSP、±dp/dtmax显著下降(P<0.05)。老龄组心室腔扩大和收缩功能障碍更显著。2)心梗后不同时间,免疫组化显示老龄组p65,p50阳性细胞数较低龄组高,差异有统计学意义(p65 400 vs 154,p50 179 vs 83,P<0.05)；Western Blot检测发现SH组及心梗3天,7天时老龄组p65蛋白表达均高于低龄组,说明老龄小鼠心梗后NF-κB活性较低龄组高。老龄组与低龄组ICAM-1表达差异均无统计学意义；老龄组VCAM-1表达SH组及心梗14天时较低龄组明显增加,差异有统计学意义(P值分别为0.001,0.034),说明年龄对VCAM-1表达有影响。
课题第二部分：1)心肌组织冰冻切片在荧光显微镜下观察,在病毒转染后第7天,可见少量eGFP阳性的心肌细胞,随着时间的延长,eGFP阳性的心肌细胞逐渐增多,转染后第21天到达高峰,转染效率约32%,持续至第28天时仍有表达。转染后第21天可见肝、骨骼肌有微量绿色荧光表达,肺、肾、脑未见明显阳性表达。Western Blot检测eGFP蛋白表达结果与荧光显微镜观察结果一致。2)心脏超声检查,rAAV9-eGFP组较生理盐水组Awd、Pwd、Aws、Pws、LVEDd、LVESd、EXLVDd、FS均无明显差异(P>0.05)。血流动力学检测,rAAV9-eGFP组较生理盐水组MAP、LVSP、LVEDP及±dp/dtmax均无明显差异(P>0.05)。
课题第三部分：1)R65+MI组死亡率及心脏破裂率(32.8% vs 15.2%,P=0.018)下降,心脏超声显示R65+MI组与MI组比较左室内径缩小、室壁厚度增加、FS值升高(P<0.05)。2)R65+MI组NF-кB活性、p65、MMP-9、MMP-2表达较MI组降低(P<0.05),TNF-α、早期VCAM-1表达较MI组低(P<0.05),IL-1β、ICAM-1表达变化不明显。3)R65+MI组CVF值较MI组低(P<0.05)。
结论：
1)老龄小鼠心脏破裂率高、心室重构重。心梗后NF-κB信号通路激活,且老龄组NF-κB活性较低龄组高,证实了NF-κB信号通路在急性心肌梗塞时的年龄异质性。2)rAAV9-eGFP经外周静脉注射21d时eGFP表达在心脏达到高峰,转染效率可达32%,可以满足大多数心脏疾病基因治疗的需要,在其他脏器表达量少或无表达,且对心功能无不良影响。3)rAAV9-R65抑制NF-κB活性,通过降低TNF-α、MMP-9、MMP-2和早期ICAM-1表达而降低胶原含量,从而降低老龄小鼠心脏破裂率并改善左室重构,进一步证实NF-κB信号通路在老龄小鼠心脏破裂及心室重构中起了重要作用。
Objective:The research is aimed at mechanisms of higher rate of cardiac rupture, more severe cardiac remodeling in old mice by study of expressions of NF-κB signal pathway post infarction, meanwhile the study is to investigate if targeted inhibition of NF-κB can attenuate post-infarct left ventricular rupture and remodeling in aged mice by ribozyme gene transfer with adeno-associated virus serotypes 9. The present study focuses on the following issues:1) To establish the acute myocardial infarction mouse model, study differential expression of p65, p50, intercelluar adhesion molecule (ICAM)-l and vascular celluar adhesion molecule (VCAM)-1 in different age groups post-infarction.2) To evaluate the transfection efficiency of recombinant adeno-associated virus serotype 9 carrying enhanced green fluorescent protein (rAAV9-eGFP) to mouse heart in vivo and the impact on cardiac function.3) To investigate if targeted inhibition of NF-κB can attenuate post-infarct left ventricular rupture and remodeling in aged mice by ribozyme gene transfer with adeno-associated virus serotypes 9. Methods: Part one:The part is about the expression of NF-κB signal pathway in mice with different age post myocardial infarction.1) The acute myocardial infarction model of mouse has been established by ligation of left coronary artery in 160 adult C57BL/6 mice (80 3-month-old,80 18-month-old) in which 20 were sham operation group (SH).Compare infarct size, rate of cardiac rupture and cardiac remodeling between different age-group. 2) Choose another 96 mice:48 3-month-old, other 48 18-month-old, set up AMI model by ligation of left coronary artery. They were randomly divided into four different groups according to time of postinfarction:SH, MI 3d,7d and 14d. The mice were sacrified at the time postinfarction according to group division and hearts were kept in liquid nitrogen then moved to-80℃refrigerator or in 4% paraformaldehyde. Expression of p65, p50 were detected by immunohistochemistry method and Western Blot, while expression of ICAM-1, VACM-1 were detected by Western Blot.Part two:1) 16 C57BL/6 mice were transfected rAAV9-eGFP by tail injection. EGFP expression in the heart, liver, lung, kidney and brain cryosections was observed under inverted fluorescence microscope 7, 14,21,28 days after the injection of rAAV9-eGFP and eGFP was quantitated by Western Blot.2) 20 C57BL/6 mice were divided into control group and rAAV9-eGFP group randomly, and were received with saline or rAAV9-eGFP. The echocardiography and hemodynamics were performed 28 days after the injection of saline or rAAV9-EGFP. Part three:1) We used 160 old mice (18-month-old) to set up acute myocardial infarction model.75 were given AAV9-R65 by tail vein injection 16 days before operation (MI+R65).75 and 10 mice were divided into myocardial infarction group (MI) and sham operation group (SH). Echocardiography was carried on 7 days post-operaion. Compare infarct size, rate of cardiac rupture and cardiac remodeling between these two groups.2) Compare activities of matrix metalloproteinases 2,9, expression of TNF-α, IL-1β, ICAM-1, VCAM-1 and content of collagen to discuss mechanisms. Results:Four results have been obtained through the study,1) There was no difference in infarct size between old and young group. Rate of cardiac rupture is higher in old group than that in young group(33.9% vs 15.6%, P=0.017). Dilation of left ventricle (LV) and contractile dysfunction were more severe in old group.2) It is observed that p65, p50 positive cells are much higher in old mice than in young mice by immunohistochemistry methods (p65 400 vs 154, p50 179 vs 83, P<0.05). Expression of p65 in SH, MI 3d,7d group in old mice is higher than in young mice, which means higher activities of NF-κB in old animals post infarction. There were no statistics differences in expression of ICAM-1 between old and young. Expression of VCAM-1 is higher in old than in young in SH and MI 14d group (P=0.001,0.034 respectively).3) eGFP expression in the heart reached the maximum at day 21, at the point of which the transduction efficiency of rAAV9-eGFP in myocardium was 32%. The other tissues had a little or no eGFP expression. The cardiac function did not reveal significant difference between rAAV9-eGFP group and the control group after transfection (P>0.05).4) Rate of cardiac rupture decreased greatly in MI+R65 group (32.8% vs 15.2%, P=0.018). Diameter of LV decrease, ventricular wall thickness, and fraction shortening increased in MI+R65 group by echocardiaography (P <0.05). Expression of MMP-9 and MMP-2, TNF-αand early VCAM-1 decreased in MI+R65 group (P<0.05). While CVF also decreased in MI+R65 group (P<0.05). But there were no changes of expression of IL-1βand ICAM-1in MI+R65 group. Inhibition of NF-κB leads to lower rate of cardiac rupture and lower expression of cytokines which identified action of NF-κB signal pathway in cardiac rupture. And age-related change in NF-κB signal pathway maybe associated with age-related cardiac rupture. Conclusions: The conclusion of the research can be drawn from the following four aspects,1) NF-κB signal pathway was activitied postinfarction and activities in old group is higher than that in young group. This result identified age-related expression differences of NF-κB signal pathway in old mice postinfarction.2) rAAV9-eGFP gene can be stably and efficiently expressed in mouse heart, and has no toxic effect on cardiac function.3) Rate of cardiac rupture and cardiac remodeling decreased greatly in old mice by ribozyme gene transfer with adeno-associated virus serotypes 9. It maybe caused by decreased collagen as the result of decreased MMP-9, MMP-2, TNF-αand early VCAM-1 which proved that NF-κB signal pathway may be associated with age-related cardiac rupture and cardiac remodeling.
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