重组腺相关病毒载体介导的人核心蛋白聚糖基因逆转自发性高血压大鼠心肌纤维化的研究
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摘要
研究背景和目的：纤维增生性疾病是导致死亡率和发病率升高的一个重要因素，同时它也影响着所有组织，器官和系统的功能。然而，尽管此类疾病给人们的健康造成极大的威胁，目前却没有有效的能针对纤维化发生机制的治疗方式。纤维化通常被定义为机体对于创伤-愈合反应失调控，是心脏及其它组织对于损伤的一种反应性应答。转化生长因子-β(transforming growth factor-β．TGF-β)是一种成纤维细胞趋化因子，可以刺激成纤维细胞增殖，增加细胞外基质蛋白(包括胶原)的合成。大量研究证明TGF-β在心肌纤维化的病因及进展中扮演重要角色。因此我们希望能找到可以阻断TGF-β生物学活性的一种特异性物质，而人核心蛋白聚糖(decorin，DCN)正是这样一种物质。DCN属于小蛋白聚糖家族中的一员，其特点是核心蛋白富含亮氨酸的重复单位。人核心蛋白聚糖被认为是TGF-β的一种天然的拮抗因子。大量实验证明DCN不仅能结合TGF-β，而且可以通过对TGF-β的生物学活性进行中和而抑制因TGF-β过度表达而引发的各个器官纤维化。随着对DCN功能和组成结构研究的不断深入，表明DCN在因过度表达TGF-β而导致的器官纤维化的防治中有着广泛的应用前景。因此我们推测DCN可能为高血压所致的心血管系统器官纤维化的治疗研究提供新的靶点。近年来，重组腺相关病毒载体(recombinant adeno-associated virus．rAAV)得到了广泛的研究和关注。rAAV能转染非分裂期和分裂期细胞，并且可以获得较为稳定，高效和长久的表达。基于上述理论基础，本研究克隆人DCN基因cDNA全长序列，测序鉴定正确后将其连接到重组腺相关病毒载体上，并在293细胞中进行病毒包装，且经过斑点杂交实验测定其滴度，最终收获能够满足我们实验所需要的高滴度的重组腺相关病毒DCN(rAAV-DCN)。然后经大鼠尾静脉转染到老年自发性高血压大鼠纤维化模型中，观察重组腺相关病毒介导的DCN基因对自发性高血压大鼠心肌纤维化的治疗作用及进一步对其相关机制进行研究。
方法：将人类DCN基因导入重组腺相关病毒载体中，并在293细胞中进行病毒包装，且经过斑点杂交实验测定其滴度，最终收获能够满足我们实验所需要的高滴度的重组腺相关病毒DCN(rAAV-DCN)。然后以已经发生心肌纤维化的四个月月龄的自发性高血压大鼠为模型，分别经尾静脉注射生理盐水1ml，rAAV-GFP和rAAV-DCN病毒(1×10~(11)pfu/只，每组7只)，在实验前及导入病毒后每2周监测一次动脉收缩压并收集一次24小时尿，共持续4个月。处死动物前经右颈总动脉插管入左心室，用美国PowerLab公司提供的心功能测定仪测定大鼠心功能的各项指标。处死动物之后提取动物心、主动脉、肝、肾等组织并置入-80℃冰箱中保存，然后提取上述组织中的总RNA和蛋白质。接着分别用RT-PCR，Western blot和ELISA方法检测DCN mRNA和蛋白质的表达和分布情况；检测不同时间段尿中微量白蛋白的含量及变化；全心及左心室称重以了解心室重构情况；肾脏，心脏石蜡包埋后用胶原染色并进行定量分析以观察肾脏和心脏纤维化情况。同时用Western blot检测TGF-β、α-SMA、p-smad2、p38MAPK和p-Akt等信号途径。
结果：1．心功能分析检测表明，导入DCN基因后可使心功能得到明显的改善，rAAV-DCN组大鼠左室收缩末压(LVESP)，左室等容收缩压最大上升速率(+dp/dt_(max))和左室等容舒张压最大下降速率(-dp/dt_(max))的绝对值较对照组和GFP组显著增加，而左室舒张末压(LVEDP)显著降低；2．Western blot检测发现导入rAAV-DCN病毒后，在心脏、肝脏和肾脏中DCN基因均有显著的表达，同时RT-PCR检测发现导入rAAV-DCN病毒后，在心脏、肝脏、肾脏和血管中均有DCN基因显著表达，除此之外，ELISA检测发现导入了rAAV-DCN病毒的动物从第2周开始直到实验终点(16周)，其血浆中的DCN水平均有较高且稳定的表达，且其表达水平要显著高于对照组；3．心脏切片的胶原染色分析结果显示：用天狼星红染色法对心肌进行胶原染色后可见对照组及GFP组心肌细胞肥大，心肌排列紊乱且可见大量胶原沉积，而导入了rAAV-DCN病毒的动物其心肌结构较为正常且仅见少量胶原沉积。这说明DCN可以预防和逆转高血压引起的心肌重构；4．心肌细胞直径测量及左心室重量与心脏重量的比值也证实了以上结果；5．导入DCN基因后的不同时间点，尿微量白蛋白的含量较对照组要明显下降，且此种作用一直持续到实验终点(16周)；6．肾脏天狼星红染色表明：对照组及GFP组可见肾脏肾小球纤维化程度明显，血管壁增厚且有大量红色胶原沉积。而DCN组较为正常，仅见少量红色胶原沉积沉积。这表明DCN可预防或明显改善老年高血压大鼠的肾脏纤维化；7．Western blot结果显示导入DCN基因后α-SMA的表达水平较对照组和GFP组显著降低；8．Western blot结果显示导入DCN基因后TGF-β、p-smad2、p38MAPK的表达水平较对照组和GFP组显著降低，而Smad6及P_(308)-Akt的表达水平较对照组和GFP组明显增高。
结论：综上所述，重组腺相关病毒载体介导的人DCN基因可以用于逆转自发性高血压大鼠心肌纤维化，且在大鼠体内高效和持续的表达，同时发挥预防和逆转高血压所致肾脏纤维化的作用。与此同时，我们观察到各组自发性高血压大鼠在实验过程中并未出现因为病毒载体注入而引起的严重毒副作用。因此本实验结果显示了重组腺相关病毒载体介导的DCN基因治疗高血压所致心脏纤维化的可行性。这为高血压伴心脏纤维化的治疗提供了全新的策略和基础。
Background and objective: Decorin (DCN), the small proteoglycan, is one memberof extracellular matrix (ECM) in the interstitial tissue and also characterized as a naturallyoccurring inhibitor that antagonizes transforming-growth factor-beta (TGF-β) which hasbeen regarded as the most important fibrotic cytokine. It has been proved that DCN canbind and neutralize extracellular TGF-βso as to inhibit organic fibrosis causing by theoverexpression of TGF-β. Thus, we conclude that DCN delivery may have therapeuticpotential for hypertensive disease. Recombinant adeno-associated virus (rAAV) has beenshown high efficiency of infecting both dividing and nondividing cells and tissues, rAAVmediated gene infection leads to stable, long-term expression without obvious immuneresponse and other adverse effects. These properties of rAAV vectors indicate that theymay constitute a powerful tool for gone therapy of chronic diseases. In the current study, weinvestigated the potential favorable effects and mechanisms of administering a recombinantadeno-associated virus (rAAV) vector expressing the DCN cDNA to reverse cardiacfibrosis in spontaneously hypertensive rats (SHR) at a dose of 1×10~(11) p.f.u, via tail vein injection.
Methods: We delivered human DCN cDNA in rAAV. The rAAV virons carryingDCN and GFP (as control) were packed by co-transfections in 293 cells and tittered by dotblots respectively. A single dose of rAAV-GFP or rAAV-DCN (about 1×10~(11) virionparticles per rat in 1 ml of saline solution) via the tail vein into the adult SHRs was injectedrespectively. Rat' blood pressure was checked every two week and 24hs urine wereharvested. All SHRs were sacrificed 16 weeks after gene delivery and measuredcardiaovascular functional indexes, including the left ventricle end-systolicpressure(LVESP) and the left ventricle end-diastolic pressure (LVEDP) and themaximal/minimum rate of LVP (±LV dp/dtmax). DCN expression in various organs ofSHRs was assessed by Western blots, reverse transcription-polymerase chain reaction(RT-PCR) and enzyme-linked immunospecific assay (ELISA). The microalbumin level inurine was analyzed by ELISA. Renal injury and the cardiovascular remodeling wereevaluated by collagen analysis. The expression of TGF-β,α-SMA, and the levels ofphosphorylation of Smad2. p38 MAPK were measured by Western blots.
Results: (1) After rAAV-mediated DCN gene administration, there were significantincreases in LVESP and +dp/dt_(max), but decreases in LVEDP and enhancement in -dp/dt_(max)as compared with controls. These data indicate an improvement in both systolic anddiastolic functions after rAAV-DCN treatment; (2) The result of Western blot, ELISA andthe reverse transcription-polymerase chain reaction (RT-PCR) showed that abundant DCNprotein and mRNA were expressed in heart, liver and kidney in rAAV-DCN treated SHRs;(3)Collagen analysis identified that DCN gene delivery reduced size of cardiomyocytes anddeposit of collagen in heart; (4) Urine microalbumin levels were significantly decresed indifferent time points after DCN gene delivery as compared with controls: (5) Collagenanalysis of kidney showed that compared with controls, DCN gene delivery significantlyimproved the deposition of collagen, attenuated glomerular sclerosis; (6) Results showedthat rAAV-DCN treatment significantly decreasedα-SMA expression in heart, consistent with its ability to inhibit ECM accumulation in heart, indicating rAAV-DCN treatmentinhibited differentiation of fibroblasts in heart in hypertensive rats; (7) Western blot showedthat rAAV-DCN treatment significantly attenuated TGF-β, p-smad2, p38MAPK andSmad6 expression in heart.
Conclusions: Based on these results, we concluded that rAAV mediated DCN genedelivery resulted in a stable and long term expression of human DCN in SHRs andalleviated cardiac as well as renal fibrosis in SHRs. Thus, it can be made a conclusion thatrAAV mediated DCN gene can be an excellent gene target for cardiac fibrosis resultingfrom hypertension.
方法：将人类DCN基因导入重组腺相关病毒载体中，并在293细胞中进行病毒包装，且经过斑点杂交实验测定其滴度，最终收获能够满足我们实验所需要的高滴度的重组腺相关病毒DCN(rAAV-DCN)。然后以已经发生心肌纤维化的四个月月龄的自发性高血压大鼠为模型，分别经尾静脉注射生理盐水1ml，rAAV-GFP和rAAV-DCN病毒(1×10~(11)pfu/只，每组7只)，在实验前及导入病毒后每2周监测一次动脉收缩压并收集一次24小时尿，共持续4个月。处死动物前经右颈总动脉插管入左心室，用美国PowerLab公司提供的心功能测定仪测定大鼠心功能的各项指标。处死动物之后提取动物心、主动脉、肝、肾等组织并置入-80℃冰箱中保存，然后提取上述组织中的总RNA和蛋白质。接着分别用RT-PCR，Western blot和ELISA方法检测DCN mRNA和蛋白质的表达和分布情况；检测不同时间段尿中微量白蛋白的含量及变化；全心及左心室称重以了解心室重构情况；肾脏，心脏石蜡包埋后用胶原染色并进行定量分析以观察肾脏和心脏纤维化情况。同时用Western blot检测TGF-β、α-SMA、p-smad2、p38MAPK和p-Akt等信号途径。
结果：1．心功能分析检测表明，导入DCN基因后可使心功能得到明显的改善，rAAV-DCN组大鼠左室收缩末压(LVESP)，左室等容收缩压最大上升速率(+dp/dt_(max))和左室等容舒张压最大下降速率(-dp/dt_(max))的绝对值较对照组和GFP组显著增加，而左室舒张末压(LVEDP)显著降低；2．Western blot检测发现导入rAAV-DCN病毒后，在心脏、肝脏和肾脏中DCN基因均有显著的表达，同时RT-PCR检测发现导入rAAV-DCN病毒后，在心脏、肝脏、肾脏和血管中均有DCN基因显著表达，除此之外，ELISA检测发现导入了rAAV-DCN病毒的动物从第2周开始直到实验终点(16周)，其血浆中的DCN水平均有较高且稳定的表达，且其表达水平要显著高于对照组；3．心脏切片的胶原染色分析结果显示：用天狼星红染色法对心肌进行胶原染色后可见对照组及GFP组心肌细胞肥大，心肌排列紊乱且可见大量胶原沉积，而导入了rAAV-DCN病毒的动物其心肌结构较为正常且仅见少量胶原沉积。这说明DCN可以预防和逆转高血压引起的心肌重构；4．心肌细胞直径测量及左心室重量与心脏重量的比值也证实了以上结果；5．导入DCN基因后的不同时间点，尿微量白蛋白的含量较对照组要明显下降，且此种作用一直持续到实验终点(16周)；6．肾脏天狼星红染色表明：对照组及GFP组可见肾脏肾小球纤维化程度明显，血管壁增厚且有大量红色胶原沉积。而DCN组较为正常，仅见少量红色胶原沉积沉积。这表明DCN可预防或明显改善老年高血压大鼠的肾脏纤维化；7．Western blot结果显示导入DCN基因后α-SMA的表达水平较对照组和GFP组显著降低；8．Western blot结果显示导入DCN基因后TGF-β、p-smad2、p38MAPK的表达水平较对照组和GFP组显著降低，而Smad6及P_(308)-Akt的表达水平较对照组和GFP组明显增高。
结论：综上所述，重组腺相关病毒载体介导的人DCN基因可以用于逆转自发性高血压大鼠心肌纤维化，且在大鼠体内高效和持续的表达，同时发挥预防和逆转高血压所致肾脏纤维化的作用。与此同时，我们观察到各组自发性高血压大鼠在实验过程中并未出现因为病毒载体注入而引起的严重毒副作用。因此本实验结果显示了重组腺相关病毒载体介导的DCN基因治疗高血压所致心脏纤维化的可行性。这为高血压伴心脏纤维化的治疗提供了全新的策略和基础。
Background and objective: Decorin (DCN), the small proteoglycan, is one memberof extracellular matrix (ECM) in the interstitial tissue and also characterized as a naturallyoccurring inhibitor that antagonizes transforming-growth factor-beta (TGF-β) which hasbeen regarded as the most important fibrotic cytokine. It has been proved that DCN canbind and neutralize extracellular TGF-βso as to inhibit organic fibrosis causing by theoverexpression of TGF-β. Thus, we conclude that DCN delivery may have therapeuticpotential for hypertensive disease. Recombinant adeno-associated virus (rAAV) has beenshown high efficiency of infecting both dividing and nondividing cells and tissues, rAAVmediated gene infection leads to stable, long-term expression without obvious immuneresponse and other adverse effects. These properties of rAAV vectors indicate that theymay constitute a powerful tool for gone therapy of chronic diseases. In the current study, weinvestigated the potential favorable effects and mechanisms of administering a recombinantadeno-associated virus (rAAV) vector expressing the DCN cDNA to reverse cardiacfibrosis in spontaneously hypertensive rats (SHR) at a dose of 1×10~(11) p.f.u, via tail vein injection.
Methods: We delivered human DCN cDNA in rAAV. The rAAV virons carryingDCN and GFP (as control) were packed by co-transfections in 293 cells and tittered by dotblots respectively. A single dose of rAAV-GFP or rAAV-DCN (about 1×10~(11) virionparticles per rat in 1 ml of saline solution) via the tail vein into the adult SHRs was injectedrespectively. Rat' blood pressure was checked every two week and 24hs urine wereharvested. All SHRs were sacrificed 16 weeks after gene delivery and measuredcardiaovascular functional indexes, including the left ventricle end-systolicpressure(LVESP) and the left ventricle end-diastolic pressure (LVEDP) and themaximal/minimum rate of LVP (±LV dp/dtmax). DCN expression in various organs ofSHRs was assessed by Western blots, reverse transcription-polymerase chain reaction(RT-PCR) and enzyme-linked immunospecific assay (ELISA). The microalbumin level inurine was analyzed by ELISA. Renal injury and the cardiovascular remodeling wereevaluated by collagen analysis. The expression of TGF-β,α-SMA, and the levels ofphosphorylation of Smad2. p38 MAPK were measured by Western blots.
Results: (1) After rAAV-mediated DCN gene administration, there were significantincreases in LVESP and +dp/dt_(max), but decreases in LVEDP and enhancement in -dp/dt_(max)as compared with controls. These data indicate an improvement in both systolic anddiastolic functions after rAAV-DCN treatment; (2) The result of Western blot, ELISA andthe reverse transcription-polymerase chain reaction (RT-PCR) showed that abundant DCNprotein and mRNA were expressed in heart, liver and kidney in rAAV-DCN treated SHRs;(3)Collagen analysis identified that DCN gene delivery reduced size of cardiomyocytes anddeposit of collagen in heart; (4) Urine microalbumin levels were significantly decresed indifferent time points after DCN gene delivery as compared with controls: (5) Collagenanalysis of kidney showed that compared with controls, DCN gene delivery significantlyimproved the deposition of collagen, attenuated glomerular sclerosis; (6) Results showedthat rAAV-DCN treatment significantly decreasedα-SMA expression in heart, consistent with its ability to inhibit ECM accumulation in heart, indicating rAAV-DCN treatmentinhibited differentiation of fibroblasts in heart in hypertensive rats; (7) Western blot showedthat rAAV-DCN treatment significantly attenuated TGF-β, p-smad2, p38MAPK andSmad6 expression in heart.
Conclusions: Based on these results, we concluded that rAAV mediated DCN genedelivery resulted in a stable and long term expression of human DCN in SHRs andalleviated cardiac as well as renal fibrosis in SHRs. Thus, it can be made a conclusion thatrAAV mediated DCN gene can be an excellent gene target for cardiac fibrosis resultingfrom hypertension.
引文
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