HIMF/FIZZ1 IN PULMONARY HYPERTENSION/RIGHT HEART FAILURE

肺动脉高压，一种病因多样但机制尚不清楚的疾病，最终 会导致右室肥厚，心力衰竭，甚至经常死亡。最近，在一个低氧诱导的模型中 关于肺动脉高压，我们发现了一种高度上调的基因，我们称之为缺氧- 诱导有丝分裂因子(HIMF)。我们发现他在重塑中表达的是增殖细胞核抗原阳性 结果表明，重组HIMF具有促有丝分裂、促血管生成和收缩血管的作用。 和趋化因子的特性。因此，Himf/FIZZ1是参与该复合体的一个新的候选基因 肺血管和右室重构之间的相互作用，这是SCCOR的中心焦点 申请。我们假设Himf是一种多价细胞因子，它介导了关键的肺细胞事件。 在高血压性肺血管重塑中，并参与适应向适应不良的转变 肺动脉高压时的右室。具体目标#1将考察HIMF/FIZZ1在 强调低氧相关重构的动物模型中肺动脉高压的机制 (慢性低氧暴露)、炎症(野百合碱)和血管异常生长(丛状病变 以及与慢性低氧和VEGF2受体抑制相结合的血管重塑)。 特殊目标#2将使用基因组、蛋白质组和生理学/药理学方法来检查 HIMF对已知的与PAH和血管相关的HIMF下游信号通路成分的影响 重塑包括炎症、生长因子/细胞周期激活、血管/血管生成和反应性 肺和心脏中氧物种的产生。特定目标#3将识别HIMF受体(S)和/或 利用蛋白质组学鉴定其相互作用组网和结合后的肺和心脏中的伙伴 肺和心脏在PAH发展过程中的翻译修饰(PTM)。具体目标#4将 探讨HIF抑制在辛伐他汀保护和逆转作用中的作用及机制 西地那非对PAH模型肺血管重构和右室重构的影响。

Pulmonary hypertension, a disease of multiple etiologies but poorly understood mechanisms, eventually leads to right ventricular hypertrophy, heart failure and often death. Recently, in a hypoxia-induced model of pulmonary hypertension, we found a gene that was highly upregulated, which we named hypoxia- induced mitogenic factor (HIMF). We found HIMF to be expressed in the remodeling PCNA positive pulmonary vessels and demonstrated that recombinant HIMF had mitogenic, angiogenic, vasoconstrictive and chemokine-like properties. HIMF/FIZZ1 is thus a novel candidate gene involved in the complex interplay between pulmonary vascular and right ventricular remodeling, a central focus of this SCCOR application. We hypothesize that HIMF is a polyvalent cytokine, which mediates critical lung cellular events in hypertensive pulmonary vascular remodeling, and is involved in the transition of adaptive to maladaptive right ventricle in pulmonary hypertension. Specific Aim #1 will examine the role of HIMF/FIZZ1 in the mechanism of pulmonary hypertension in animal models that emphasize hypoxia-related remodeling (chronic hypoxia exposure), inflammation (monocrotaline) and abnormal vessel growth (plexiform lesions and vascular remodeling associated with combined chronic hypoxia and VEGF2 receptor inhibition). Specific Aim #2 will use genomic, proteomic, and physiologic/pharmacologic approaches to examine HIMF effect on components of known downstream HIMF signaling pathways related to PAH and vascular remodeling including inflammation, growth factors/cell cycle activation, angio/vasculogenesis and reactive oxygen species generation in lung and heart. Specific Aim #3 will identify the HIMF receptor(s) and/or binding partners in lung and heart utilizing proteomics to identify its interactome network and post- translational modifications (PTMs) in lung and heart during the development of PAH. Specific Aim #4 will investigate the role and mechanism of HIMF inhibition in the protective and reversal actions of simvastatin and sildenafil on pulmonary vascular remodeling and right ventricular remodeling in models of PAH.