NOTCH-1在主动脉瓣二叶畸形合并升主动脉扩张发生中的作用机制研究
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摘要
研究背景与目的
主动脉瓣二叶畸形（Bicuspid Aortic Valve, BAV）是常见的先天性心脏畸形，在普通人群中的发病率大约在0.46%－1.37%，男女比率约为3:1。BAV患者可终身没有症状，若是合并主动脉病变如升主动脉扩张（Ascending aortic dilation, AAD）、升主动脉瘤（Ascending aortic aneurysm, AAA）或主动脉夹层（Aortic dissection,AD），则手术治疗风险和治疗费用显著增加，术后并发症发生率和死亡率增高。因此探讨BAV合并AAD的发生机制，不仅对疾病的早期诊断、早期治疗提供指导，还可以为今后BAV合并AAD的生物治疗提供潜在靶点。
目前普遍认为，主动脉血管中层平滑肌细胞（Vascular smooth muscle cell，VSMC）的功能异常与主动脉病变的发生密切相关。VSMC是血管中层的主要细胞类型，现有研究表明VSMC凋亡、表型转化和高分泌MMPs导致动脉血管结构破坏，细胞迁移增加和细胞外基质降低，最终导致AAD发生。但是，对于VSMC功能异常的机制仍不明确，尤其是BAV合并AAD的具体机制目前未见报道。
NOTCH信号通路是人体内高度保守的跨膜信号传导通路，其在调控细胞增殖、分化和凋亡的过程中发挥重要作用。淋巴瘤、胶质瘤、非小细胞癌和胰腺癌等肿瘤细胞的凋亡与NOTCH-1基因相关，当NOTCH-1下调时，肿瘤细胞的凋亡增加，这也成为许多肿瘤治疗的研究靶点。现有研究发现，在胚胎心脏发育过程中，NOTCH-1在调控内皮细胞向间叶细胞转化（Epithelial-mesenchymal transition，EMT）中发挥重要作用，而EMT是胚胎期瓣膜发育的重要环节。已有研究表明，NOTCH-1基因异常导致信号传导障碍不仅导致BAV的发生，而且与远期瓣膜钙盐沉积及钙化相关。但是NOTCH-1基因的表达改变是否也调控VSMC的功能从而影响主动脉壁功能以及其中的可能机制目前尚未见报道。
本实验旨在通过回顾本院近20年入院手术BAV患者的临床资料，总结BAV发病的流行病学特点，分析其合并症特别是AAD的临床特点，研究引起AAD的高危因素，为今后的临床诊治提供依据。在此基础上，以临床病理及组织标本为切入点，分析BAV合并AAD的分子病理学特征，了解NOTCH-1基因在BAV合并AAD发病中的作用，并在细胞学水平验证NOTCH-1基因改变与血管平滑肌细胞功能改变的联系，提出其可能的分子机制，为BAV合并AAD的预防与治疗提供理论支持。
研究方法和结果
为以上目的，本研究分为以下四个部分：
1、分析总结20年在院手术治疗的BAV患者的临床资料，包括患者性别、年龄、体表面积（BSA）、术前合并症、心功能等级，以及术前重要的超声检查指标，根据瓣膜解剖特点确定分型。分析不同性别及不同瓣膜分型在临床特点、合并症方面有无差异。并在此基础上，采用二元Logistic回归分析对升主动脉扩张的危险因素进行分析，得出BAV合并AAD的危险因素。
统计结果显示，BAV患者以男性占多数，主要的临床合并症包括瓣膜功能障碍、感染性心内膜炎和升主动脉病变等。最为常见合并的先天性心脏病为主动脉缩窄和室间隔缺损。在瓣膜分型中，以左-右冠瓣融合型（L-R型）最为常见，占63.3%，其次为右-无冠瓣融合型（R-N型），占32.8%。全组406例患者在院死亡率为6.2%，要高于同期其他在院因主动脉瓣病变手术患者，合并感染性心内膜炎是导致在院死亡率增大因素之一。性别差异影响到BAV患者的临床特点，入院手术时男性患者的年龄明显低于女性患者，并且男性患者更易合并有SBE。男性患者表现出更差的心脏功能，而女性患者则更常表现出合并有升主动脉病变。不同瓣膜分型在临床特点上也有差异：L-R型患者易同时累及升主动脉，而对于R-N型患者，瓣膜功能障碍更易出现。通过Logistic回归分析，我们发现年龄增加和女性是BAV合并AAD的独立危险因素。
2、通过分析BAV患者升主动脉标本的病理标本，总结其组织学特征和细胞外基质成分的分子生物学改变，采用脱氧核糖核苷酸末端转移酶介导的缺口末端标记（Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay,TUNEL）染色法检测BAV组和TAV组与正常对照组中主动脉壁中层细胞凋亡率的差异。免疫组化分析基质金属蛋白酶-2,9（Matrix metalloproteinase, MMP）的表达情况，并采用qRT-PCR检测标本中的NOTCH-1、VSMC分化迁移标志蛋白在分子水平表达情况。最后，根据NOTCH-1的表达情况，将BAV合并AAD组分成NOTCH-1表达正常组和低表达组，分别比较两组间细胞凋亡率、MMP-2,9及VSMC分化标志蛋白的表达差异。
经过研究，我们发现，相比于正常对照组，BAV合并AAD患者的主动脉壁结构破坏、平滑肌细胞的丢失增多。维多利亚蓝染色（Victoria blue, VB）显示BAV主动脉壁中的红色胶原纤维含量增高而蓝色的弹力纤维断裂、含量降低。免疫组化结果可见BAV和TAV合并AAD患者的MMP-2,9表达显著高于正常对照组。TUNEL染色见正常主动脉壁中仅有少量凋亡细胞，而在BAV合并AAD组和TAV合并AAD中，凋亡明显增多，并且主动脉扩张程度越重，中层VSMC凋亡越多。qRT-PCR检测提示，NOTCH-1基因在BAV/N组和BAV/AAD组中明显低于对照组（P<0.01），在TAV/AAD组中低于对照组（P<0.05）。代表活化收缩型VSMC的α-SMA和SM22α的表达明显降低，而调节细胞外基质成分代谢的MMP-2,9则明显上调。我们还发现，NOTCH-1表达下调与VSMC凋亡及表型转化相关。相比与NOTCH-1正常组，在NOTCH-1下调组中，平滑肌细胞凋亡率显著增高，α-SMA和SM22α的表达显著降低，但MMP-2,9的表达无统计学差异。
3、为了研究BAV相关的目的基因NOTCH-1在调控VSMC凋亡中的作用机制，我们首先通过体外成功培养可用于细胞学实验的VSMC，并采用化学合成法构建NOTCH-1的siRNA，通过脂质体转染成功下调NOTCH-1表达。在此基础上我们通过Annexin-V/PI双标记流式细胞仪检测细胞凋亡率的变化，并通过qRT-PCR和Western blot分别检测凋亡相关蛋白在mRNA水平和蛋白水平的变化，从不同凋亡通路分析其参与的可能性，从而得出NOTCH-1调控VSMC凋亡的主要机制。
实验结果显示，相比siRNA阴性对照组， NOTCH-1siRNA转染组细胞凋亡率显著提高，凋亡相关的蛋白也有相应的变化。siRNA实验组的促凋亡蛋白Caspase-9和Bax显著提高，而抑制凋亡蛋白BCL-2及NF-Kappa B显著降低；另一方面Caspase-8的表达也有升高，但不如其他凋亡蛋白的表达变化程度大。因此，我们认为，NOTCH-1调控VSMC凋亡主要通过线粒体途径完成，但也不排除受体介导途径在其中的作用。
4、我们在体外培养大鼠VSMC及转染NOTCH-1siRNA的基础上，采用qRT-PCR和Western blot方法检测NOTCH-1siRNA组和阴性转染组间VSMC表型转化标志基因α-SMA和SM22α的表达差异，分析NOTCH-1基因下调对VSMC分化的影响。利用Transwell迁移实验研究分析VSMC迁移能力的变化，同时检测MMP-2,9的表达情况，分析MMPs表达受NOTCH-1下调的影响及其对VSMC迁移能力的影响。
通过研究我们发现，NOTCH-1下调后可诱导VSMC由收缩亚型向合成亚型转化，α-SMA和SM22α的表达在siRNA组中显著下降。伴随着NOTCH-1表达下调，VSMC细胞迁移能力增加，但影响细胞迁移能力的MMP-2,9并无显著上升，提示NOTCH-1调控VSMC迁移能力改变主要是通过改变细胞的分化状态而不是通过影响MMPs的表达，NOTCH-1对MMP-2,9的表达无直接的调控作用。
结论
1、BAV患者男女比例约为2.6：1，最常见的合并症有瓣膜功能异常、感染性心内膜炎（12.5%），升主动脉扩张（44.1%）。伴发最常见的先天性心脏病为主动脉缩窄和室间隔缺损。在二叶瓣分型中最常见的是L-R融合型（占63.3%），其次为R-N融合型（占32.8%）；
2、男性BAV患者更易发生AI，且易并发感染性心内膜炎；而女性患者更易发生AS。女性患者更加容易并发升主动脉扩张。L-R型BAV患者易并发升主动脉扩张和主动脉窦部扩张，并且更易出现AI，而R-N型患者更易发展成为AS合并AI；
3、影响BAV患者合并升主动脉的独立危险因素包括年龄增加和女性，因合并感染性心内膜炎而早期就诊是起到一定保护性作用；
4、BAV合并AAD的基本组织病理改变是中层囊性坏死，包括平滑肌细胞肿胀、变性、缺失，弹力蛋白断裂、消失，且病理改变的严重程度与主动脉扩张的程度存在一定的关联；
5、NOTCH-1表达下调、VSMC的凋亡增加及表型转化、MMP-2,9的表达与BAV合并AAD的发生具有相关性；
6、NOTCH-1的表达下调与VSMC凋亡增加、表型转化具有相关性；
7、NOTCH-1表达下调可促进VSMC凋亡增加，线粒体凋亡通路的相关蛋白表达有显著差异提示其发挥了重要作用，但不排除受体介导通路在其中发挥的作用。
8、NOTCH-1表达下调可诱导VSMC由收缩型向合成型转化，收缩型VSMC的标志蛋白α-SMA和SM22Α表达下调；
9、NOTCH-1对MMP-2,9的表达没有直接调控作用，NOTCH-1表达下调时，MMP-2,9表达变化无明显差异；
10、NOTCH-1表达下调可促进VSMC迁移力增加，与细胞表型转化相关，而与MMP-2,9的表达无直接联系。
Background and objective:Bicuspid aortic valve (BAV) disease is the mostcommon congenital heart defect, with a prevalence estimated between0.46%and1.37%.There is a male predominance of approximately3:1. For the reason that BAV patients canbe healthy in their whole life with no symptoms, they are difficult to be diagnosed. Most ofthem are made a definite diagnosis when visiting the hospital due to the other complication,such as valve dysfunction, infective endocarditis, and ascending aortic disease. Comparedwith another congenital heart disease, BAV patients face more difficulty for diagnosis andtreatment. When facing aortic lesions such as ascending aortic dilation, aortic aneurysm oraortic dissection, surgery risk and cost of treatment is a significant increase coupled withthe increasing of the incidence of postoperative complications and mortality. Therefore, themechanism of BAV complicated with AAD is not only to provide guidance on the earlydiagnosis and early treatment of disease, but also to provides a potential target for thebiological therapy of BAV complicated with AAD.
It is widely believed that the dysfunction of vascular smooth muscle cells (VSMC) isrelevant to AAD. VSMC is the main component of the vascular media, which play animportant role in maintaining vascular integrity and function. In the other hand, VSMCsalso secrete the aortic wall extracellular matrix proteins, including collagen, elastin,laminin. But it is unknown that what make the VSMC dysfunction.
The Notch pathway is an evolutionarily conserved signaling mechanism that playsessential roles both during development and in the maintenance of adult tissue homeostasisin metazoan. In the process of heart embryo development, NOTCH-1play an importantrole in the regulating endothelial cells to mesenchymal transformation (EMT), which is thekey pathway of the aortic valve development. Mutations in the NOTCH1result inabnormal aortic valve development (BAV) and later to de-repression of calcium deposition.But it is unknown whether is the NOTCH-1gene participate in aortopathy progress.
The purpose of this experiment is to review our hospital database (from Jan1991to Dec2010) of BAV patient, summarize epidemiological characteristics, analysize of its complications’ clinical feature, particularly the ascending aortic dilation. Based on this, weanalysize the risk factors of BAV complicated with AAD, and then provide the advice forclinical diagnosis and treatment in the future. Secondly, we analysize the pathologicalchange of the clinical tissue to find out the effect of NOTCH-1and VSMC function on thepathogenesis of BAV complicated with AAD. Thirdly, by means of cytological method weanalysize the relation between NOTCH1gene change and VSMC function.
Methods and results:The present study was divided into six sections.
1.Clinical retrospective analysis of406cases of bicuspid aortic valve disease.The20years’ clinical data of surgical treatment of BAV patients was summarized,including patients gender, age, body surface area (BSA), preoperative complications,cardiac function level, and preoperative ultrasound examination index, BAV phenotype.Analysis the difference in clinical features and comorbidity according to gender and BAVphenotype. And on this basis, the binary Logistic regression analysis was use to search forthe risk factor of BAV complicated with AAD.
Through analysis, we found that BAV patients with male-dominated major clinicalcomplications include valve dysfunction and infective endocarditis and ascending aorticdisease. The most common complication of congenital heart disease is coarctation of theaorta and ventricular septal defect. The most common aortic valve phenotype is theleft-right coronary valve fusion (L-R type), accounting for63.3%, followed by theright-noncoronary valve fusion type (R-N type), accounted for32.8%. The in-hospitalmortality of whole406patients was6.2%, which is higher than the other surgical aorticvalve disease in the same period. Preoperative infective endocarditis is one of the riskfactors of hospital mortality.
Gender affect the clinical features of BAV patients, the age of male patients admitting tothe hospital was obviously lower than that of the female patients, and male patients weremore likely to complicated with SBE. The male patients showed worse cardiac function,and female patients tend to progressed aortic lesion. Aortic valve phenotype effect clinicalcharacteristics: type L-R is tend to involve aortic disease, otherwise type R-N is tend toinvolve valve dysfunction. Through the Logistic regression analysis, we found thatincreasing age and female is an independent risk factor of the the BAV complicated with AAD.
2.Correlation study between NOTCH-1expression or VSMC function change andBAV complicated AAD.By analyzing the pathological change of BAV patients’ aorta, we found out the histologicfeatures and extracellular matrix components of molecular biological change. Using theTUNEL method to compare the media VSMC apoptosis rate between BAV group andcontrol group. Immunohistochemical analysis of matrix metalloproteinase-2(MMP-2) andvascular smooth muscle α actin protein (α-SMA), and qRT-PCR detection expression ofNOTCH-1, apoptosis-related protein and VSMC differentiation migration marker proteinsin fresh specimens.
Researches show that compared with normal control group the the BAV with AAD patientshave more damage about aortic wall structure, and the more loss of smooth muscle cells.Victoria blue (VB) staining show that red collagen fiber content increased and blue elasticfiber fracture in BAV aortic wall. Immunohistochemical results reveal that the MMP-2expression was significantly higher in the BAV and TAV complicated with AAD patientsthan the normal control group, which represents high α-SMA expression than in theBAV/TAV AAD group. TUNEL staining in the normal aortic wall show only a fewapoptotic cells, otherwise an increasing number apoptosis cell in the the the BAV/TAVAAD group, and the more severe degree of aortic dilatation, the more middle VSMCapoptosis. qRT-PCR detect that the expression of NOTCH-1genes in the BAV/N andBAV/AAD group was significantly lower than the control group (P <0.01), and inTAV/AAD group was lower than the control group (P <0.05). α-SMA,and SM22αexpression, which is on behalf of the contractile phenotype of VSMC, was significantlyreduced, and the MMP-2,9expression, which regulate the metabolism of extracellularmatrix components, is significantly up-regulated.
3. The mechanism of NOTCH-1regulate smooth muscle cell apoptosis.
To investigate the mechanism of NOTCH-1regulate VSMC apoptosis, firstly wesuccessfully culture VSMC in vitro which can be used for the cytological experiments, andthen chemically synthesize NOTCH-1siRNA to down-regulate its expression by lipofectintransfect. Base on those, we use Annexin-V/PI double labeling method to detect cell apoptosis rate, and use qRT-PCR and Western blot method to detect apoptosis-relatedprotein change in the mRNA and protein levels.
VSMC with NOTCH-1siRNA have significantly increased apoptosis rate, correspondingwith apoptosis related proteins changing. Compared to the control group, the expression ofpro-apoptosis proteins Caspase-9and Bax in the siRNA group increased significantly,while the expression of anti-apoptosis proteins BCL-2and NF-Kappa B significantlyreduced; On the other hand, the expression of Caspase-8of of the have increased, but notas good as the degree of the other apoptotic proteins. Therefore, we draw the conclusionthat NOTCH-1regulate VSMC apoptosis mainly through mitochondrial pathway, but thedeath-receptor pathway is not excluded.
4.The effect of NOTCH-1on VSMC migration and differentiation.
Based on last experiment, we use qRT-PCR and Western blot to compare the expression ofα-SMA and SM22α, which is VSMC phenotype transformation marker gene, betweenNOTCH-1siRNA group and negative control group. Transwell migration experiment wasto assess the changes in VSMC migration ability, on the same time, the expression ofMMP-2,9were detected to analyze the effect of NOTCH-1on them.
The researches reveals that in the siRNA group with the significant down-express ofNOTCH-1the VSMC transfer from contractile subtypes to the synthesis subtype,manifesting that the expression of α-SMA and SM22α reduced. Accompanied withNOTCH-1down-regulated the VSMC migration ability increased, but the MMP-2,9haveno significant rise. The reason mainly is that the VSMC migration ability is not effected bythe expression of MMPs but by the cell differentiation state. NOTCH-1do not regulate theexpression of MMP-2,9in direct effect.
Conclusion:
1.BAV patients with male to female ratio is approximately2.6:1, the most commoncomplication is valve dysfunction, infective endocarditis and ascending aortic dilatation.The most common congenital heart disease associated with BAV is coarctation of the aortaand ventricular septal defect. The most common aortic valve phenotype is the L-R fusion(63.3%), followed by R-N fusion (32.8%).
2.Male BAV patients are more susceptible to AI and infective endocarditis; and femalepatients are more likely to possess AS. Female patients tend to progress ascending aorticdilation. BAV patients with type L-R may predispose to the expansion of the ascendingaortic dilation and aortic sinus dilation, and are more vulnerable to the AI, while the typeR-N BAV patients are easier to develop with AS and AI.
3.The independent risk factors of BAV patients with ascending aortic dilation includeincreasing age and women. Because of complicated with infective endocarditis, earlytreatment is to play a passive effect.
4.The pathological changes of BAV/AAD patients is the cystic medial necrosis, includingsmooth muscle cell swelling, degeneration, lackage of elastin, and the severity ofpathological changes was correlated with the extent of aortic dilatation.
5. The down-regulation of NOTCH-1, more apoptosis and phenotypic change of VSMC,the expression of MMP-2,9are relevant to the BAV complicated with AAD.
6. The down-regulation of NOTCH-1is relevant to more apoptosis and phenotypic changeof VSMC.
7.The down-regulation of NOTCH-1may promote VSMC apoptosis, the mitochondrialpathway of apoptosis played an important role, but does not exclude the role ofdeath-receptor pathway.
8.The down-regulation of NOTCH-1could induce the conversion of VSMC fromcontractile subtype to synthetic subtype, with the down-regulation of α-SMA and SM22α.
9.NOTCH-1do not regulate the expression of MMP-2,9in direct effect. When theexpression of NOTCH-1down-regulate, the expression of MMP-2was no significantchange.
10.The down-regulation of NOTCH-1can promote VSMC migration through not the up-expression of MMP-2,9but the the cell differentiation state.
主动脉瓣二叶畸形（Bicuspid Aortic Valve, BAV）是常见的先天性心脏畸形，在普通人群中的发病率大约在0.46%－1.37%，男女比率约为3:1。BAV患者可终身没有症状，若是合并主动脉病变如升主动脉扩张（Ascending aortic dilation, AAD）、升主动脉瘤（Ascending aortic aneurysm, AAA）或主动脉夹层（Aortic dissection,AD），则手术治疗风险和治疗费用显著增加，术后并发症发生率和死亡率增高。因此探讨BAV合并AAD的发生机制，不仅对疾病的早期诊断、早期治疗提供指导，还可以为今后BAV合并AAD的生物治疗提供潜在靶点。
目前普遍认为，主动脉血管中层平滑肌细胞（Vascular smooth muscle cell，VSMC）的功能异常与主动脉病变的发生密切相关。VSMC是血管中层的主要细胞类型，现有研究表明VSMC凋亡、表型转化和高分泌MMPs导致动脉血管结构破坏，细胞迁移增加和细胞外基质降低，最终导致AAD发生。但是，对于VSMC功能异常的机制仍不明确，尤其是BAV合并AAD的具体机制目前未见报道。
NOTCH信号通路是人体内高度保守的跨膜信号传导通路，其在调控细胞增殖、分化和凋亡的过程中发挥重要作用。淋巴瘤、胶质瘤、非小细胞癌和胰腺癌等肿瘤细胞的凋亡与NOTCH-1基因相关，当NOTCH-1下调时，肿瘤细胞的凋亡增加，这也成为许多肿瘤治疗的研究靶点。现有研究发现，在胚胎心脏发育过程中，NOTCH-1在调控内皮细胞向间叶细胞转化（Epithelial-mesenchymal transition，EMT）中发挥重要作用，而EMT是胚胎期瓣膜发育的重要环节。已有研究表明，NOTCH-1基因异常导致信号传导障碍不仅导致BAV的发生，而且与远期瓣膜钙盐沉积及钙化相关。但是NOTCH-1基因的表达改变是否也调控VSMC的功能从而影响主动脉壁功能以及其中的可能机制目前尚未见报道。
本实验旨在通过回顾本院近20年入院手术BAV患者的临床资料，总结BAV发病的流行病学特点，分析其合并症特别是AAD的临床特点，研究引起AAD的高危因素，为今后的临床诊治提供依据。在此基础上，以临床病理及组织标本为切入点，分析BAV合并AAD的分子病理学特征，了解NOTCH-1基因在BAV合并AAD发病中的作用，并在细胞学水平验证NOTCH-1基因改变与血管平滑肌细胞功能改变的联系，提出其可能的分子机制，为BAV合并AAD的预防与治疗提供理论支持。
研究方法和结果
为以上目的，本研究分为以下四个部分：
1、分析总结20年在院手术治疗的BAV患者的临床资料，包括患者性别、年龄、体表面积（BSA）、术前合并症、心功能等级，以及术前重要的超声检查指标，根据瓣膜解剖特点确定分型。分析不同性别及不同瓣膜分型在临床特点、合并症方面有无差异。并在此基础上，采用二元Logistic回归分析对升主动脉扩张的危险因素进行分析，得出BAV合并AAD的危险因素。
统计结果显示，BAV患者以男性占多数，主要的临床合并症包括瓣膜功能障碍、感染性心内膜炎和升主动脉病变等。最为常见合并的先天性心脏病为主动脉缩窄和室间隔缺损。在瓣膜分型中，以左-右冠瓣融合型（L-R型）最为常见，占63.3%，其次为右-无冠瓣融合型（R-N型），占32.8%。全组406例患者在院死亡率为6.2%，要高于同期其他在院因主动脉瓣病变手术患者，合并感染性心内膜炎是导致在院死亡率增大因素之一。性别差异影响到BAV患者的临床特点，入院手术时男性患者的年龄明显低于女性患者，并且男性患者更易合并有SBE。男性患者表现出更差的心脏功能，而女性患者则更常表现出合并有升主动脉病变。不同瓣膜分型在临床特点上也有差异：L-R型患者易同时累及升主动脉，而对于R-N型患者，瓣膜功能障碍更易出现。通过Logistic回归分析，我们发现年龄增加和女性是BAV合并AAD的独立危险因素。
2、通过分析BAV患者升主动脉标本的病理标本，总结其组织学特征和细胞外基质成分的分子生物学改变，采用脱氧核糖核苷酸末端转移酶介导的缺口末端标记（Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay,TUNEL）染色法检测BAV组和TAV组与正常对照组中主动脉壁中层细胞凋亡率的差异。免疫组化分析基质金属蛋白酶-2,9（Matrix metalloproteinase, MMP）的表达情况，并采用qRT-PCR检测标本中的NOTCH-1、VSMC分化迁移标志蛋白在分子水平表达情况。最后，根据NOTCH-1的表达情况，将BAV合并AAD组分成NOTCH-1表达正常组和低表达组，分别比较两组间细胞凋亡率、MMP-2,9及VSMC分化标志蛋白的表达差异。
经过研究，我们发现，相比于正常对照组，BAV合并AAD患者的主动脉壁结构破坏、平滑肌细胞的丢失增多。维多利亚蓝染色（Victoria blue, VB）显示BAV主动脉壁中的红色胶原纤维含量增高而蓝色的弹力纤维断裂、含量降低。免疫组化结果可见BAV和TAV合并AAD患者的MMP-2,9表达显著高于正常对照组。TUNEL染色见正常主动脉壁中仅有少量凋亡细胞，而在BAV合并AAD组和TAV合并AAD中，凋亡明显增多，并且主动脉扩张程度越重，中层VSMC凋亡越多。qRT-PCR检测提示，NOTCH-1基因在BAV/N组和BAV/AAD组中明显低于对照组（P<0.01），在TAV/AAD组中低于对照组（P<0.05）。代表活化收缩型VSMC的α-SMA和SM22α的表达明显降低，而调节细胞外基质成分代谢的MMP-2,9则明显上调。我们还发现，NOTCH-1表达下调与VSMC凋亡及表型转化相关。相比与NOTCH-1正常组，在NOTCH-1下调组中，平滑肌细胞凋亡率显著增高，α-SMA和SM22α的表达显著降低，但MMP-2,9的表达无统计学差异。
3、为了研究BAV相关的目的基因NOTCH-1在调控VSMC凋亡中的作用机制，我们首先通过体外成功培养可用于细胞学实验的VSMC，并采用化学合成法构建NOTCH-1的siRNA，通过脂质体转染成功下调NOTCH-1表达。在此基础上我们通过Annexin-V/PI双标记流式细胞仪检测细胞凋亡率的变化，并通过qRT-PCR和Western blot分别检测凋亡相关蛋白在mRNA水平和蛋白水平的变化，从不同凋亡通路分析其参与的可能性，从而得出NOTCH-1调控VSMC凋亡的主要机制。
实验结果显示，相比siRNA阴性对照组， NOTCH-1siRNA转染组细胞凋亡率显著提高，凋亡相关的蛋白也有相应的变化。siRNA实验组的促凋亡蛋白Caspase-9和Bax显著提高，而抑制凋亡蛋白BCL-2及NF-Kappa B显著降低；另一方面Caspase-8的表达也有升高，但不如其他凋亡蛋白的表达变化程度大。因此，我们认为，NOTCH-1调控VSMC凋亡主要通过线粒体途径完成，但也不排除受体介导途径在其中的作用。
4、我们在体外培养大鼠VSMC及转染NOTCH-1siRNA的基础上，采用qRT-PCR和Western blot方法检测NOTCH-1siRNA组和阴性转染组间VSMC表型转化标志基因α-SMA和SM22α的表达差异，分析NOTCH-1基因下调对VSMC分化的影响。利用Transwell迁移实验研究分析VSMC迁移能力的变化，同时检测MMP-2,9的表达情况，分析MMPs表达受NOTCH-1下调的影响及其对VSMC迁移能力的影响。
通过研究我们发现，NOTCH-1下调后可诱导VSMC由收缩亚型向合成亚型转化，α-SMA和SM22α的表达在siRNA组中显著下降。伴随着NOTCH-1表达下调，VSMC细胞迁移能力增加，但影响细胞迁移能力的MMP-2,9并无显著上升，提示NOTCH-1调控VSMC迁移能力改变主要是通过改变细胞的分化状态而不是通过影响MMPs的表达，NOTCH-1对MMP-2,9的表达无直接的调控作用。
结论
1、BAV患者男女比例约为2.6：1，最常见的合并症有瓣膜功能异常、感染性心内膜炎（12.5%），升主动脉扩张（44.1%）。伴发最常见的先天性心脏病为主动脉缩窄和室间隔缺损。在二叶瓣分型中最常见的是L-R融合型（占63.3%），其次为R-N融合型（占32.8%）；
2、男性BAV患者更易发生AI，且易并发感染性心内膜炎；而女性患者更易发生AS。女性患者更加容易并发升主动脉扩张。L-R型BAV患者易并发升主动脉扩张和主动脉窦部扩张，并且更易出现AI，而R-N型患者更易发展成为AS合并AI；
3、影响BAV患者合并升主动脉的独立危险因素包括年龄增加和女性，因合并感染性心内膜炎而早期就诊是起到一定保护性作用；
4、BAV合并AAD的基本组织病理改变是中层囊性坏死，包括平滑肌细胞肿胀、变性、缺失，弹力蛋白断裂、消失，且病理改变的严重程度与主动脉扩张的程度存在一定的关联；
5、NOTCH-1表达下调、VSMC的凋亡增加及表型转化、MMP-2,9的表达与BAV合并AAD的发生具有相关性；
6、NOTCH-1的表达下调与VSMC凋亡增加、表型转化具有相关性；
7、NOTCH-1表达下调可促进VSMC凋亡增加，线粒体凋亡通路的相关蛋白表达有显著差异提示其发挥了重要作用，但不排除受体介导通路在其中发挥的作用。
8、NOTCH-1表达下调可诱导VSMC由收缩型向合成型转化，收缩型VSMC的标志蛋白α-SMA和SM22Α表达下调；
9、NOTCH-1对MMP-2,9的表达没有直接调控作用，NOTCH-1表达下调时，MMP-2,9表达变化无明显差异；
10、NOTCH-1表达下调可促进VSMC迁移力增加，与细胞表型转化相关，而与MMP-2,9的表达无直接联系。
Background and objective:Bicuspid aortic valve (BAV) disease is the mostcommon congenital heart defect, with a prevalence estimated between0.46%and1.37%.There is a male predominance of approximately3:1. For the reason that BAV patients canbe healthy in their whole life with no symptoms, they are difficult to be diagnosed. Most ofthem are made a definite diagnosis when visiting the hospital due to the other complication,such as valve dysfunction, infective endocarditis, and ascending aortic disease. Comparedwith another congenital heart disease, BAV patients face more difficulty for diagnosis andtreatment. When facing aortic lesions such as ascending aortic dilation, aortic aneurysm oraortic dissection, surgery risk and cost of treatment is a significant increase coupled withthe increasing of the incidence of postoperative complications and mortality. Therefore, themechanism of BAV complicated with AAD is not only to provide guidance on the earlydiagnosis and early treatment of disease, but also to provides a potential target for thebiological therapy of BAV complicated with AAD.
It is widely believed that the dysfunction of vascular smooth muscle cells (VSMC) isrelevant to AAD. VSMC is the main component of the vascular media, which play animportant role in maintaining vascular integrity and function. In the other hand, VSMCsalso secrete the aortic wall extracellular matrix proteins, including collagen, elastin,laminin. But it is unknown that what make the VSMC dysfunction.
The Notch pathway is an evolutionarily conserved signaling mechanism that playsessential roles both during development and in the maintenance of adult tissue homeostasisin metazoan. In the process of heart embryo development, NOTCH-1play an importantrole in the regulating endothelial cells to mesenchymal transformation (EMT), which is thekey pathway of the aortic valve development. Mutations in the NOTCH1result inabnormal aortic valve development (BAV) and later to de-repression of calcium deposition.But it is unknown whether is the NOTCH-1gene participate in aortopathy progress.
The purpose of this experiment is to review our hospital database (from Jan1991to Dec2010) of BAV patient, summarize epidemiological characteristics, analysize of its complications’ clinical feature, particularly the ascending aortic dilation. Based on this, weanalysize the risk factors of BAV complicated with AAD, and then provide the advice forclinical diagnosis and treatment in the future. Secondly, we analysize the pathologicalchange of the clinical tissue to find out the effect of NOTCH-1and VSMC function on thepathogenesis of BAV complicated with AAD. Thirdly, by means of cytological method weanalysize the relation between NOTCH1gene change and VSMC function.
Methods and results:The present study was divided into six sections.
1.Clinical retrospective analysis of406cases of bicuspid aortic valve disease.The20years’ clinical data of surgical treatment of BAV patients was summarized,including patients gender, age, body surface area (BSA), preoperative complications,cardiac function level, and preoperative ultrasound examination index, BAV phenotype.Analysis the difference in clinical features and comorbidity according to gender and BAVphenotype. And on this basis, the binary Logistic regression analysis was use to search forthe risk factor of BAV complicated with AAD.
Through analysis, we found that BAV patients with male-dominated major clinicalcomplications include valve dysfunction and infective endocarditis and ascending aorticdisease. The most common complication of congenital heart disease is coarctation of theaorta and ventricular septal defect. The most common aortic valve phenotype is theleft-right coronary valve fusion (L-R type), accounting for63.3%, followed by theright-noncoronary valve fusion type (R-N type), accounted for32.8%. The in-hospitalmortality of whole406patients was6.2%, which is higher than the other surgical aorticvalve disease in the same period. Preoperative infective endocarditis is one of the riskfactors of hospital mortality.
Gender affect the clinical features of BAV patients, the age of male patients admitting tothe hospital was obviously lower than that of the female patients, and male patients weremore likely to complicated with SBE. The male patients showed worse cardiac function,and female patients tend to progressed aortic lesion. Aortic valve phenotype effect clinicalcharacteristics: type L-R is tend to involve aortic disease, otherwise type R-N is tend toinvolve valve dysfunction. Through the Logistic regression analysis, we found thatincreasing age and female is an independent risk factor of the the BAV complicated with AAD.
2.Correlation study between NOTCH-1expression or VSMC function change andBAV complicated AAD.By analyzing the pathological change of BAV patients’ aorta, we found out the histologicfeatures and extracellular matrix components of molecular biological change. Using theTUNEL method to compare the media VSMC apoptosis rate between BAV group andcontrol group. Immunohistochemical analysis of matrix metalloproteinase-2(MMP-2) andvascular smooth muscle α actin protein (α-SMA), and qRT-PCR detection expression ofNOTCH-1, apoptosis-related protein and VSMC differentiation migration marker proteinsin fresh specimens.
Researches show that compared with normal control group the the BAV with AAD patientshave more damage about aortic wall structure, and the more loss of smooth muscle cells.Victoria blue (VB) staining show that red collagen fiber content increased and blue elasticfiber fracture in BAV aortic wall. Immunohistochemical results reveal that the MMP-2expression was significantly higher in the BAV and TAV complicated with AAD patientsthan the normal control group, which represents high α-SMA expression than in theBAV/TAV AAD group. TUNEL staining in the normal aortic wall show only a fewapoptotic cells, otherwise an increasing number apoptosis cell in the the the BAV/TAVAAD group, and the more severe degree of aortic dilatation, the more middle VSMCapoptosis. qRT-PCR detect that the expression of NOTCH-1genes in the BAV/N andBAV/AAD group was significantly lower than the control group (P <0.01), and inTAV/AAD group was lower than the control group (P <0.05). α-SMA,and SM22αexpression, which is on behalf of the contractile phenotype of VSMC, was significantlyreduced, and the MMP-2,9expression, which regulate the metabolism of extracellularmatrix components, is significantly up-regulated.
3. The mechanism of NOTCH-1regulate smooth muscle cell apoptosis.
To investigate the mechanism of NOTCH-1regulate VSMC apoptosis, firstly wesuccessfully culture VSMC in vitro which can be used for the cytological experiments, andthen chemically synthesize NOTCH-1siRNA to down-regulate its expression by lipofectintransfect. Base on those, we use Annexin-V/PI double labeling method to detect cell apoptosis rate, and use qRT-PCR and Western blot method to detect apoptosis-relatedprotein change in the mRNA and protein levels.
VSMC with NOTCH-1siRNA have significantly increased apoptosis rate, correspondingwith apoptosis related proteins changing. Compared to the control group, the expression ofpro-apoptosis proteins Caspase-9and Bax in the siRNA group increased significantly,while the expression of anti-apoptosis proteins BCL-2and NF-Kappa B significantlyreduced; On the other hand, the expression of Caspase-8of of the have increased, but notas good as the degree of the other apoptotic proteins. Therefore, we draw the conclusionthat NOTCH-1regulate VSMC apoptosis mainly through mitochondrial pathway, but thedeath-receptor pathway is not excluded.
4.The effect of NOTCH-1on VSMC migration and differentiation.
Based on last experiment, we use qRT-PCR and Western blot to compare the expression ofα-SMA and SM22α, which is VSMC phenotype transformation marker gene, betweenNOTCH-1siRNA group and negative control group. Transwell migration experiment wasto assess the changes in VSMC migration ability, on the same time, the expression ofMMP-2,9were detected to analyze the effect of NOTCH-1on them.
The researches reveals that in the siRNA group with the significant down-express ofNOTCH-1the VSMC transfer from contractile subtypes to the synthesis subtype,manifesting that the expression of α-SMA and SM22α reduced. Accompanied withNOTCH-1down-regulated the VSMC migration ability increased, but the MMP-2,9haveno significant rise. The reason mainly is that the VSMC migration ability is not effected bythe expression of MMPs but by the cell differentiation state. NOTCH-1do not regulate theexpression of MMP-2,9in direct effect.
Conclusion:
1.BAV patients with male to female ratio is approximately2.6:1, the most commoncomplication is valve dysfunction, infective endocarditis and ascending aortic dilatation.The most common congenital heart disease associated with BAV is coarctation of the aortaand ventricular septal defect. The most common aortic valve phenotype is the L-R fusion(63.3%), followed by R-N fusion (32.8%).
2.Male BAV patients are more susceptible to AI and infective endocarditis; and femalepatients are more likely to possess AS. Female patients tend to progress ascending aorticdilation. BAV patients with type L-R may predispose to the expansion of the ascendingaortic dilation and aortic sinus dilation, and are more vulnerable to the AI, while the typeR-N BAV patients are easier to develop with AS and AI.
3.The independent risk factors of BAV patients with ascending aortic dilation includeincreasing age and women. Because of complicated with infective endocarditis, earlytreatment is to play a passive effect.
4.The pathological changes of BAV/AAD patients is the cystic medial necrosis, includingsmooth muscle cell swelling, degeneration, lackage of elastin, and the severity ofpathological changes was correlated with the extent of aortic dilatation.
5. The down-regulation of NOTCH-1, more apoptosis and phenotypic change of VSMC,the expression of MMP-2,9are relevant to the BAV complicated with AAD.
6. The down-regulation of NOTCH-1is relevant to more apoptosis and phenotypic changeof VSMC.
7.The down-regulation of NOTCH-1may promote VSMC apoptosis, the mitochondrialpathway of apoptosis played an important role, but does not exclude the role ofdeath-receptor pathway.
8.The down-regulation of NOTCH-1could induce the conversion of VSMC fromcontractile subtype to synthetic subtype, with the down-regulation of α-SMA and SM22α.
9.NOTCH-1do not regulate the expression of MMP-2,9in direct effect. When theexpression of NOTCH-1down-regulate, the expression of MMP-2was no significantchange.
10.The down-regulation of NOTCH-1can promote VSMC migration through not the up-expression of MMP-2,9but the the cell differentiation state.
引文
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