CARDIOVASCULAR REMODELING MEDIATED BY RXRa RECEPTORS

在美国，每年与心内膜缓冲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]。管状心脏的增殖、分化和凋亡过程整合形成四室器官的分子机制尚不清楚。心内膜缓冲组织重构为瓣膜结构的复杂过程涉及心肌、内皮细胞、间充质细胞、神经嵴和心外膜起源的多种细胞系。在流出道和房室管中，从上皮到间充质到缓冲组织的转化和心肌化等重塑事件是这些过程精确协调的结果。维甲酸x受体α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缺陷的原因方面显示出相当大的希望。在胚胎日(E) 13.5时，RXRalpha-KO胚胎表现出类似于人类先天性心脏缺陷的心内膜融合组织和室室畸形频谱[3.5]。初步证据表明，rxrα - ko胚胎心脏增殖减少，细胞凋亡增加。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rxrα在流出道、房室管和心室心肌的缓冲组织重塑过程中整合了增殖、分化和凋亡的过程，而tgf - β 2以依赖rxrα的方式参与了这些过程。本研究的具体目的是：1)验证conotruncal和房室缓冲中上皮细胞向间充质细胞转化依赖于rxralpha的假设。II)确定RXRalpha在颈干和脑室分离过程中增殖和凋亡过程中的作用。III)为了验证在心脏发生过程中RXRalpha表达的中断导致TGFbeta2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.