CARDIOVASCULAR REMODELING MEDIATED BY RXRa RECEPTORS

在美国，每年与心内膜垫组织形成和重塑相关的心血管缺陷占先天性心脏病的很大比例[1.2]。整合增殖、分化和凋亡过程以适当重塑管状心脏以形成四腔器官的分子机制尚不清楚。与将内膜垫组织重塑为瓣膜结构相关的复杂过程涉及心肌、内皮、间充质、神经嵴和心外膜起源的多个细胞谱系。重塑事件，如上皮细胞到间充质转化为缓冲组织和流出道和房室管中的心肌化是这些过程精确协调的结果。类维生素A X受体α基因敲除（RXRalpha-KO）小鼠模型在澄清这些关系和帮助确定先天性心脏病的原因方面显示出相当大的希望。在胚胎第13.5天（E），RXRalpha-KO胚胎显示出一系列类似于人类先天性心脏病的内膜融合组织和室腔畸形[3.5]。初步证据表明，在RXRalpha-KO胚胎心脏中存在减少的增殖和增加的凋亡。此外，在RXRalpha-KO胚胎中，我们发现心脏中TGF-β 2 mRNA和蛋白水平升高。因此，我们的假设是，RXR α的功能，以整合在流出道，AV管和心室心肌的垫组织重塑过程中的增殖，分化和凋亡的过程中，TGF-β 2有助于这些过程中的RXR α依赖性的方式。本提案的具体目的是：1）验证圆锥干和房室垫中上皮细胞向间充质细胞转化是RXRa依赖性的假设。II）确定RXR α在锥体干和心室腔分隔期间增殖和凋亡过程中的作用。III）检验心脏发生过程中RXR α表达的破坏导致TGF β 2依赖性心脏缺陷的假设。

Cardiovascular defects associated with the formation and remodeling of endocardial cushion tissue accounts for a large proportion of congenital heart disease in the United States each year [1.2]. The molecular mechanisms integrating the processes of proliferation, differentiation, and apoptosis for proper remodeling of the tubular heart to form the four- chambered organ is not clear. The complex processes associated with remodeling of endocardial cushion tissue into valvular structures involves multiple cell lineages of myocardial, endothelial, mesenchymal, neural crest, and epicardial origins. Remodeling events such as epithelial-to- mesenchymal transformation to cushion tissue and myocardialization in the outflow tract and atrioventricular canal are the result of a precise coordination of these processes. The retinoid X-receptor alpha knockout (RXRalpha-KO) mouse model shows considerable promise at clarifying these relationships and aiding in the determination of the causes of congenital heart defects. At embryonic day (E) 13.5, RXRalpha-KO embryos display a spectrum of endocardial fusion tissue and ventricular chamber malformations analogous to human congenital heart defects [3.5]. Preliminary evidence indicates there is a reduced proliferation and increased apoptosis in RXRalpha-KO embryonic hearts. Moreover,, in RXRalpha-KO embryos, we found elevated levels of TGF-beta2 mRNA and protein in the heart. Thus, our hypothesis is that RXRalpha functions to integrate the processes of proliferation, differentiation, and apoptosis during remodeling of cushion tissue in the outflow tract, AV canal, and ventricular myocardium and that TGF-beta2 contributes to these processes in an RXRalpha-dependent manner. The Specific Aims of this proposal are: 1) To test the hypothesis that epithelial-to-mesenchymal cell transformation in the conotruncal and atrioventricular cushions is RXRalpha-dependent. II) To determine the role of RXRalpha in the processes of proliferation and apoptosis during septation of the conotruncus and ventricular chambers. III) To test the hypothesis that disruption of RXRalpha expression during cardiogenesis results in cardiac defects that are TGFbeta2 dependent.