Abstract：
Small muscular pulmonary artery remodeling is a dominant feature of pulmonary arterial hypertension (PAH). PSEN1 affects angiogenesis, cancer, and Alzheimer\'s disease. We aimed to determine the role of PSEN1 in the pathogenesis of vascular remodeling in pulmonary hypertension (PH). Hemodynamics and vascular remodeling in the Psen1-knockin and smooth muscle-specific Psen1-knockout mice were assessed. The functional partners of PSEN1 were predicted by bioinformatics analysis and biochemical experiments. The therapeutic effect of PH was evaluated by administration of the PSEN1-specific inhibitor ELN318463. We discovered that both the mRNA and protein levels of PSEN1 were increased over time in hypoxic rats, monocrotaline rats, and Su5416/hypoxia mice. Psen1 transgenic mice were highly susceptible to PH, whereas smooth muscle-specific Psen1-knockout mice were resistant to hypoxic PH. STRING analysis showed that Notch1/2/3, β-catenin, Cadherin-1, DNER (delta/notch-like epidermal growth factor-related receptor), TMP10, and ERBB4 appeared to be highly correlated with PSEN1. Immunoprecipitation confirmed that PSEN1 interacts with β-catenin and DNER, and these interactions were suppressed by the catalytic PSEN1 mutations D257A, D385A, and C410Y. PSEN1 was found to mediate the nuclear translocation of the Notch1 intracellular domains and activated RBP-Jκ. Octaarginine-coated liposome-mediated pharmacological inhibition of PSEN1 significantly prevented and reversed the pathological process in hypoxic and monocrotaline-induced PH. PSEN1 essentially drives the pathogenesis of PAH and interacted with the noncanonical Notch ligand DNER. PSEN1 can be used as a promising molecular target for treating PAH. PSEN1 inhibitor ELN318463 can prevent and reverse the progression of PH and can be developed as a potential anti-PAH drug.
摘要：
小肌性肺动脉重塑是PAH的主要特征。PSEN1影响血管生成，癌症和阿尔茨海默病。我们旨在确定PSEN1在PH中血管重塑的发病机理中的作用。评估了Psen1敲入和平滑肌特异性Psen1敲除小鼠的血液动力学和血管重塑。通过生物信息学分析和生化实验预测了PSEN1的功能伴侣。通过施用PSEN1特异性抑制剂ELN318463评估PH的治疗效果。我们发现PSEN1的mRNA和蛋白质水平在低氧大鼠中随着时间的推移而增加，野百合碱(MCT)大鼠和Su5416/缺氧(SuHx)小鼠。Psen1转基因小鼠对PH高度易感，而平滑肌特异性Psen1基因敲除小鼠对低氧PH具有抗性。STRING分析表明，Notch1/2/3，β-catenin，Cadherin-1,DNER,TMP10和ERBB4似乎与PSEN1高度相关。免疫沉淀证实PSEN1与β-catenin和DNER相互作用，这些相互作用被催化PSEN1突变D257A抑制，D385A和C410Y。发现PSEN1介导Notch1细胞内结构域的核易位并激活RBP-Jκ。八精氨酸包被的脂质体介导的PSEN1药理学抑制可明显预防和逆转低氧和MCT诱导的PH的病理过程。PSEN1基本上驱动PAH的发病机理并与非规范Notch配体DNER相互作用。PSEN1可以用作治疗PAH的有希望的分子靶标。PSEN1抑制剂ELN318463可以预防和逆转PH的进展，并被开发为潜在的抗PAH药物。
