腺相关病毒介导的内皮型一氧化氮合酶在高血压基因治疗中的实验研究
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摘要
高血压是一种常见病、多发病,如何有效控制血压已成为医学界普遍关注的焦点之一。本研究旨在观察腺相关病毒载体介导的内皮型一氧化氮合酶(eNOS)基因对自发性高血压大鼠(SHR)血压的影响及对心脏、肾脏等靶器官的保护作用,为临床高血压基因治疗奠定理论基础。本研究以自发性高血压大鼠为研究对象,通过尾静脉注射腺相关病毒介导的eNOS(AAV-eNOS)进行干预,结果发现AAV-eNOS在SHR体内至少可稳定表达4周,经AAV-eNOS治疗2周后,血压可明显降低,并可持续至4周后,除明显的降压作用外,可明显降低心脏及肾脏组织胶原含量,延缓或抑制纤维化进程;同时,免疫组化及原位杂交结果显示,AAV-eNOS治疗后可明显降低心脏及肾脏组织中AT1 mRNA及蛋白表达水平,提示AAV-eNOS基因治疗高血压可能与其抑制靶器官AT1的表达、从而阻断Ang II的缩血管作用有关;TUNEL检测结果显示AAV-eNOS治疗可明显抑制心肌及肾脏组织细胞的凋亡,从而延缓器官纤维化进程,保护靶器官功能。因此,我们考虑AAV-eNOS可能成为高血压治疗的一个新手段。
Hypertension is defined as the abnormal occurrence which means the arterial blood pressure is above the normal value. How to control the blood pressure effectively has been one of the facal points which generally attract the attention in medical science because the hypertension has been become a common and frequent encountered disease. The present investigation aimed to observe the influence of blood pressure and the protection of the target organs by the endothelial nitricoxide synthase (eNOS) in spontaneous hypertension rat (SHR), and do some contribution to theory base for the clinic gene therapy to hypertension.
The SHR rats were divided into SHR group, AAV-LacZ group, and AAV-eNOS group, and choose WKY rats as negative control group (WKY group) which has normal blood pressure. The AAV-eNOS group were injected AAV-eNOS 200μl which contains 1×1012 eNOS copy through tail vein, AAV-LacZ group were injected AAV-LacZ 200μl which contains no eNOS gene copy, and the rats in WKY and SHR group were injected 0.1 mol·L-1 PBS solution 200μl. The blood pressure were observed once a week till the 4th week. All the rats were sacrificed at the end of 4th week, and the heart and right kidney were collected into the 4 % polyoxymethylene solution. The immunohistochemistry and in situ hybridyzation were applied to detect eNOS and AT1 protein and mRNA expression, TUNEL were also used to evaluate the cell apoptosis in the heart and kidney. We got these results from this research:
1. After the treatment of AAV-eNOS, there was no distinguished difference among the body weight, heart weight, and left venturicular weight in each group; also no obvious difference was found in cardiac index, left-ventricular index in all the groups.
2. Two weeks after the treatment of AAV-eNOS, the blood pressure of AAV-eNOS group had been decreased significantly (P<0.05) compared with SHR group; after 4 weeks, the blood pressure of AAV-eNOS group had been decreased to normal level, compared with SHR group, there is significant difference (P<0.05).
3. In WKY treatment group, the cardiac muscle fibers line up in order, transverse striations is clear, there is a clear nucleus, and no cell swelling, a wealth capillary network and a small number of fibroblasts could be seen between the cardiac muscle. In the SHR group, fibroblast proliferation of cardiac muscle, fibrous tissue accrementing obviously, myocardial fibrosis slightly, after AAV-eNOS treatment, myocardial fibrosis mitigate significantly. In WKY group, no obvious abnormality was found in glomerulus of kidney, nephric tubule and kidney arteriole. While in SHR group, the glomerulus of kidney generate fibrous degeneration and hyalinization (glomerulus of kidney express homogeneous red dye whith no structure), volume minification, peripheral glomcrulus hypertrophy comply, the wall of glomerulus arteriole became thickening, renal tubular cell swelling, lumina stenosis, interstitial fibrosis manifest in the area of serious pathological changes. The AAV-eNOS treatment group, the structure of glomerulus and nephric tubule is generally normal, the endomembrane of renal arterioles wall is smooth, interstitial fibrosis proliferation decreased significantly.
4. Immunohistochemistry results: In WKY group, eNOS express signal could be seen in the myocardial cell endochylema,while in SHR group the express of eNOS is lower than WKY group significantly. The expression of eNOS significantly increased in AAV-eNOS treated group.
The expression of eNOS protein in kidney showed no significant differences in each group. The positive signals of AT1 expression could be seen in the myocardial cell endochylema while in SHR group, the expression of AT1 is lower significantly than WKY group (P<0.05). The expression of AT1 significantly decreased in AAV-eNOS treated group compared with SHR group (P<0.05); The positive signals of AT 1 expression could be seen in renal tubular cells in WKY group and was lower than SHR group significantly (P<0.05).
5. The results of eNOS in situ hybridization showed that, there was basic expression of eNOS mRNA in myocardial tissue of WKY group; The expression of eNOS mRNA was increased significantly in AAV-eNOS treatment group compared with SHR group (P<0.05).
There was basic expression of eNOS mRNA in kidney in WKY group; The expression of eNOS mRNA increased significantly in AAV-eNOS treatment group compared with SHR group (P<0.05).
6.The results of AT1 in situ hybridization showed that, there were basic expression of AT1 mRNA both in myocardial and kidney tissue in WKY group. The expression of AT1 mRNA significantly increased in the myocardial and renal interstitial tissue of SHR group compared with the WKY group (P<0.05), at the end of the experiment, The expression of eNOS mRNA in myocardial and renal interstitial tissue of AAV-eNOS treatment group was significantly lower than SHR group (P<0.05).
7.The results of TUNEL show that:Compared with WKY group, The expression of staining positive signal in myocardial and renal interstitial tissue of SHR group increased significantly (P<0.05), while decreased significantly in AAV-eNOS group(P<0.05).
Conclusions:
1. The recombinant adenovirus vector carrying eNOS gene can be integrated into heart and kidney tissues of SHR and could be stablely expressed.
2. After AAV-eNOS induced into SHR, it can reduce blood pressure effectively and sustain for more than 2 weeks.
3. AAV-eNOS gene therapy can delay or inhibit fibrosis of the target organs caused by hypertension, and inhibit myocardial reconstruction and renal interstitial fibrosis.
4. AAV-eNOS gene therapy successfully treating in hypertension may be related to inhibition of expression of AT1 in target organs, thereby block the vasoconstriction effects of Ang II.
5. AAV-eNOS gene therapy can inhibit the apoptosis of heart and kidney and protect target organs.
Hypertension is defined as the abnormal occurrence which means the arterial blood pressure is above the normal value. How to control the blood pressure effectively has been one of the facal points which generally attract the attention in medical science because the hypertension has been become a common and frequent encountered disease. The present investigation aimed to observe the influence of blood pressure and the protection of the target organs by the endothelial nitricoxide synthase (eNOS) in spontaneous hypertension rat (SHR), and do some contribution to theory base for the clinic gene therapy to hypertension.
The SHR rats were divided into SHR group, AAV-LacZ group, and AAV-eNOS group, and choose WKY rats as negative control group (WKY group) which has normal blood pressure. The AAV-eNOS group were injected AAV-eNOS 200μl which contains 1×1012 eNOS copy through tail vein, AAV-LacZ group were injected AAV-LacZ 200μl which contains no eNOS gene copy, and the rats in WKY and SHR group were injected 0.1 mol·L-1 PBS solution 200μl. The blood pressure were observed once a week till the 4th week. All the rats were sacrificed at the end of 4th week, and the heart and right kidney were collected into the 4 % polyoxymethylene solution. The immunohistochemistry and in situ hybridyzation were applied to detect eNOS and AT1 protein and mRNA expression, TUNEL were also used to evaluate the cell apoptosis in the heart and kidney. We got these results from this research:
1. After the treatment of AAV-eNOS, there was no distinguished difference among the body weight, heart weight, and left venturicular weight in each group; also no obvious difference was found in cardiac index, left-ventricular index in all the groups.
2. Two weeks after the treatment of AAV-eNOS, the blood pressure of AAV-eNOS group had been decreased significantly (P<0.05) compared with SHR group; after 4 weeks, the blood pressure of AAV-eNOS group had been decreased to normal level, compared with SHR group, there is significant difference (P<0.05).
3. In WKY treatment group, the cardiac muscle fibers line up in order, transverse striations is clear, there is a clear nucleus, and no cell swelling, a wealth capillary network and a small number of fibroblasts could be seen between the cardiac muscle. In the SHR group, fibroblast proliferation of cardiac muscle, fibrous tissue accrementing obviously, myocardial fibrosis slightly, after AAV-eNOS treatment, myocardial fibrosis mitigate significantly. In WKY group, no obvious abnormality was found in glomerulus of kidney, nephric tubule and kidney arteriole. While in SHR group, the glomerulus of kidney generate fibrous degeneration and hyalinization (glomerulus of kidney express homogeneous red dye whith no structure), volume minification, peripheral glomcrulus hypertrophy comply, the wall of glomerulus arteriole became thickening, renal tubular cell swelling, lumina stenosis, interstitial fibrosis manifest in the area of serious pathological changes. The AAV-eNOS treatment group, the structure of glomerulus and nephric tubule is generally normal, the endomembrane of renal arterioles wall is smooth, interstitial fibrosis proliferation decreased significantly.
4. Immunohistochemistry results: In WKY group, eNOS express signal could be seen in the myocardial cell endochylema,while in SHR group the express of eNOS is lower than WKY group significantly. The expression of eNOS significantly increased in AAV-eNOS treated group.
The expression of eNOS protein in kidney showed no significant differences in each group. The positive signals of AT1 expression could be seen in the myocardial cell endochylema while in SHR group, the expression of AT1 is lower significantly than WKY group (P<0.05). The expression of AT1 significantly decreased in AAV-eNOS treated group compared with SHR group (P<0.05); The positive signals of AT 1 expression could be seen in renal tubular cells in WKY group and was lower than SHR group significantly (P<0.05).
5. The results of eNOS in situ hybridization showed that, there was basic expression of eNOS mRNA in myocardial tissue of WKY group; The expression of eNOS mRNA was increased significantly in AAV-eNOS treatment group compared with SHR group (P<0.05).
There was basic expression of eNOS mRNA in kidney in WKY group; The expression of eNOS mRNA increased significantly in AAV-eNOS treatment group compared with SHR group (P<0.05).
6.The results of AT1 in situ hybridization showed that, there were basic expression of AT1 mRNA both in myocardial and kidney tissue in WKY group. The expression of AT1 mRNA significantly increased in the myocardial and renal interstitial tissue of SHR group compared with the WKY group (P<0.05), at the end of the experiment, The expression of eNOS mRNA in myocardial and renal interstitial tissue of AAV-eNOS treatment group was significantly lower than SHR group (P<0.05).
7.The results of TUNEL show that:Compared with WKY group, The expression of staining positive signal in myocardial and renal interstitial tissue of SHR group increased significantly (P<0.05), while decreased significantly in AAV-eNOS group(P<0.05).
Conclusions:
1. The recombinant adenovirus vector carrying eNOS gene can be integrated into heart and kidney tissues of SHR and could be stablely expressed.
2. After AAV-eNOS induced into SHR, it can reduce blood pressure effectively and sustain for more than 2 weeks.
3. AAV-eNOS gene therapy can delay or inhibit fibrosis of the target organs caused by hypertension, and inhibit myocardial reconstruction and renal interstitial fibrosis.
4. AAV-eNOS gene therapy successfully treating in hypertension may be related to inhibition of expression of AT1 in target organs, thereby block the vasoconstriction effects of Ang II.
5. AAV-eNOS gene therapy can inhibit the apoptosis of heart and kidney and protect target organs.
引文
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