PDF(Pubmed)
Abstract：
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway.
摘要：
肺动脉高压（PAH）是一种慢性疾病，其特征是平均肺动脉压逐渐升高。已经在家族性PAH中描述了BMPR2和AQP1基因的突变。骨形态发生蛋白BMP9和BMP10以高亲和力与BMPR2结合。BMP9的给药已被提议作为针对PAH的潜在治疗策略。尽管最近相互矛盾的证据对这种做法的效果提出了质疑。考虑到上述分子参与PAH的发病，programming,和治疗价值，我们在体外研究了BMP9，BMPR2和AQP1对人肺微血管内皮细胞中BMP9，BMP10，BMPR2，AQP1和TGFB1表达的影响。我们的结果表明，沉默BMPR2基因导致其两个主要配体的表达增加，即BMP9和BMP10。外源性给予BMP9导致BMP10恢复到基础水平，同时恢复了由BMPR2沉默引起的AQP1蛋白水平下降和TGFB1mRNA和蛋白表达水平下降。此外，AQP1基因沉默也导致BMP9和BMP10的表达增加。我们的结果可能暗示外源施用BMP9对参与BMP信号通路的分子的影响可能取决于BMPR2的表达水平。一起来看,这些结果可能有助于深入了解BMP信号通路的高度复杂的相互作用.
