OBJECTIVE Pulmonary arterial hypertension (PAH) is a fatal disease characterized by the narrowing of pulmonary arteries (PAs). It is now established that this phenotype is associated with enhanced PA smooth muscle cells (PASMCs) proliferation and suppressed apoptosis. This phenotype is sustained in part by the activation of several DNA repair pathways allowing PASMCs to survive despite the unfavorable environmental conditions. PIM1 (Moloney murine leukemia provirus integration site) is an oncoprotein upregulated in PAH and involved in many prosurvival pathways, including DNA repair. The objective of this study was to demonstrate the implication of PIM1 in the DNA damage response and the beneficial effect of its inhibition by pharmacological inhibitors in human PAH-PASMCs and in rat PAH models. Approach and Results: We found in vitro that PIM1 inhibition by either SGI-1776, TP-3654, siRNA (silencer RNA) decreased the phosphorylation of its newly identified direct target KU70 (lupus Ku autoantigen protein p70) resulting in the inhibition of double-strand break repair (Comet Assay) by the nonhomologous end-joining as well as reduction of PAH-PASMCs proliferation (Ki67-positive cells) and resistance to apoptosis (Annexin V positive cells) of PAH-PASMCs. In vivo, SGI-1776 and TP-3654 given 3× a week, improved significantly pulmonary hemodynamics (right heart catheterization) and vascular remodeling (Elastica van Gieson) in monocrotaline and Fawn-Hooded rat models of PAH. CONCLUSIONS We demonstrated that PIM1 phosphorylates KU70 and initiates DNA repair signaling in PAH-PASMCs and that PIM1 inhibitors represent a therapeutic option for patients with PAH.

中文翻译：

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PIM1（莫洛尼鼠白血病原病毒整合位点）抑制作用可降低肺动脉高压中非同源末端连接DNA损伤修复信号通路。

目的肺动脉高压（PAH）是一种致命疾病，其特征是肺动脉（PAs）变窄。现在确定该表型与增强的PA平滑肌细胞（PASMC）增殖和抑制的凋亡相关。这种表型在一定程度上是由于几种DNA修复途径的激活而得以维持的，即使环境条件不利，PASMC仍然能够生存。PIM1（莫洛尼鼠白血病原病毒整合位点）是一种在PAH中上调的癌蛋白，并参与许多生存途径，包括DNA修复。这项研究的目的是证明在人PAH-PASMC和大鼠PAH模型中，PIM1在DNA损伤应答中的意义以及药理抑制剂对其抑制的有益作用。方法和结果：我们在体外发现，SGI-1776，TP-3654，siRNA（沉默子RNA）对PIM1的抑制作用会降低其新近鉴定的直接靶标KU70（狼疮Ku自身抗原蛋白p70）的磷酸化，从而抑制双链断裂修复（通过非同源末端连接以及减少PAH-PASMCs的PAH-PASMCs增殖（Ki67阳性细胞）和抗凋亡（Annexin V阳性细胞）来进行彗星分析。在体内，每周服用3次的SGI-1776和TP-3654在PAH的单crocrotaline和Fawn-Hooded大鼠模型中显着改善了肺血液动力学（右心导管插入术）和血管重构（Elastica van Gieson）。结论我们证明了PIM1使KU70磷酸化并启动了PAH-PASMC中的DNA修复信号传导，并且PIM1抑制剂代表了PAH患者的治疗选择。