Molecular mechanism vascular remodeling and blood pressure regulation by orphan receptor, and theraputic

肾素是一种重要的心血管内稳态酶，受cAMP的调节。我们以前的研究表明，肾素基因的表达至少部分地受到基因5‘侧翼区的一个新的作用DNA元件(CNRE)的调控。我们在这里使用酵母单杂交克隆系统证明了CNRE结合蛋白是人LXRa的小鼠同源物。LxRα是核受体转录调控超家族的成员之一，与该家族的另一成员RxRα一起作为异源二聚体发挥作用。为了研究LXRα对肾素基因表达的影响，我们将LXRα表达载体导入肾素产生细胞As4.1。LXRα在As4.1细胞中的瞬时过表达使cAMP可诱导含有CNRE的报告构建体。此外，在稳定转染LXRα后，As4.1细胞显示cAMP诱导的肾素基因表达上调，并显著增加与cnre的核结合活性，这一作用可被…拮抗。更像是抗LXRα抗体。有趣的是，LXRα还可以与c-myc启动子中的同源cNRE结合，并介导cAMP诱导的c-myc表达。LXRα是一种新的cAMP反应性的肾素和c-myc基因表达的核调节剂，它的发现不仅为深入了解其在核受体信号通路中的作用提供了新的思路，而且也为理解心血管疾病的病理生理机制提供了新的思路。为了研究LXRα在心血管重塑中的病理生理作用，我们采用了聚乙烯袖套诱导的小鼠股动脉血管损伤模型。我们发现，LXRα的反式激活与c-myc和肾素的表达增加以及新生内膜的增生有关。我们还观察到LXRα在压力超负荷诱导的小鼠心肌肥厚中表达上调。此外，我们还证明了肾素-血管紧张素系统的激活在这些模型小鼠的心血管重塑中起着重要作用。这些结果表明，LXRα在心血管重塑中具有重要的病理生理意义，LXRα有望成为心血管疾病基因治疗的新靶点。较少

Renin, an enzyme important in cardiovascular homeostasis, is regulated by cAMP. Our previous studies suggested that renin gene expression is regulated, at least partly, by a novel as acting DNA element (CNRE) in the gene's 5'-flanking region. We demonstrate here that a CNRE binding protein is the mouse homologue of human LXRa using a yeast one-hybrid cloning system. LXRα is a member of the superfamily of nuclear receptor regulators of transcription and functions as a heterodimer with RXRα, another member of this family. To examine the function of LXRα on the expression of renin gene, we transfected the renin-producing renal As4.1 cells with LXRα expression plasmid. Transient overexpression of LXRα in As4.1 cells confers cAMP inducibility to reporter constructs containing the CNRE. Moreover, following stable transfection of LXRα, As4.1 cells show a cAMP-inducible upregulation of renin mRNA expression with a significant increase in nuclear binding activity to CNRE, which is antagonized b … More y an anti-LXRα antibody. Interestingly, LXRα can also bind to the homologous CNRE in the c-myc promoter and mediate cAMP-inducible c-myc expression. The identification of LXRα as a novel cAMP responsive nuclear modulator of renin and c-myc gene expression should provide new insights not only into its role in nuclear receptor-signaling pathway, but also in the understanding of cardiovascular pathophysiology. To examine the pathophysiological roles of LXRα in cardiovascular remodeling, we employed polyethylene cuff-induced vascular injury model in me femoral artery mouse model. We found that LXRα was transactivated associated with the increase in the expression of c-myc and renin, and neointimal hyperplasia. We also observed that LXRα was upregulated in pressure-overload-induced cardiac hypertrophy in mice. Moreover, we demonstrated that activation of renin-angiotensin system is important in the cardiovascular remodeling in these mouse models. These results suggest the pathophysiological importance of LXRα in cardiovascular remodeling and LXRα can be a future target for gene therapy for cardiovascular diseases. Less