DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

DAMP 信号介导 HIMF 诱导的肺动脉高压

• 批准号: 9976575
• 负责人: Roger A Johns
• 金额: $ 45.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976575
• 关键词: Acetylation; Animal Model; Apoptosis; Attenuated; Autophagocytosis; BMPR2 gene; Biological; Blood Vessels; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Clinical; Cytokine Signaling; Cytoplasm; Development; Diabetes Mellitus; Disease; Down-Regulation; Epigenetic Process; Etiology; Event; Exocytosis; FOXO1A gene; Feedback; Functional disorder; Gene Expression; Genetic Transcription; Goals; HMGB1 Protein; HMGB1 gene; Histologic; Homologous Gene; Human; Hypoxia; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-2; Lead; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Modification; Molecular; Mus; Nuclear; Nuclear Translocation; Pathologic; Patients; Pattern; Peripheral Blood Mononuclear Cell; Play; Process; Production; Property; Proteins; Publishing; Pulmonary Hypertension; Pulmonary artery structure; Receptor Activation; Regulation; Resistance; Rodent; Rodent Model; Role; S100 Calcium Binding Protein; S100 Proteins; S100A11 gene; SIRT1 gene; Scleroderma; Serum; Signal Transduction; Signaling Molecule; Signaling Protein; Slide; Smooth Muscle Myocytes; Specimen; Structure of parenchyma of lung; Vascular remodeling; Work; autocrine; bone morphogenetic protein receptors; cell motility; clinically significant; diagnostic biomarker; extracellular; hemodynamics; immunoregulation; in vivo; mouse resistin-like alpha; novel therapeutic intervention; novel therapeutics; paracrine; receptor for advanced glycation endproducts; resistin; response; trafficking; vascular inflammation

SUMMARY Hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-) is critical to pulmonary hypertension (PH) development in rodent models, and our work suggests that HIMF may trigger a positive feedback loop to amplify the vascular inflammation required for remodeling. We have implicated the human homolog of HIMF, human resistin (hresistin) in human idiopathic and scleroderma related PH. Several downstream vascular and immune processes critical to rodent and human PH are activated by HIMF and hresistin but the manner in which HIMF/hresistin initiates these responses in a pathologic manner remains unknown. Damage-associated molecular pattern molecules (DAMPs), including high mobility group box (HMGB)1 and S100 calcium binding proteins, act as endogenous danger signals to regulate the subsequent inflammatory response through an autocrine and paracrine manner via activation of the receptor for advanced glycation end-products (RAGE). We now show HIMF and hresistin-induced HMGB1 and S100A11 activation in human vascular and immune cells related to PH and in PH animal models. However the mechanism of HIMF/hresistin regulation of this response and the function of the HIMF/DAMP/RAGE signaling axis during PH development remain unclear. In preliminary studies, we found that HIMF signaling activates HMGB1/RAGE axis in vivo and in vitro in association with suppressed sirtuin (Sirt)1, enhanced autophagy, attenuated expression of forkhead box O (FoxO)1 and bone morphogenetic protein receptor (BMPR)2, and hyper- proliferation of pulmonary artery smooth muscle cells (PASMC). In addition, in our preliminary studies another DAMP, the S100A11, also has been found to increase in peripheral blood mononuclear cells of PH patients. In this proposal, we hypothesize that HIMF/hresistin activated DAMP signaling mediates the cross- talk between vascular cells and immune cells, initiates an autophagic response, and downregulates FoxO1 and BMPR2, thereby contributing to PH pathophysiology. We will investigate the role of DAMPs in HIMF-induced inflammatory response and subsequent vascular remodeling by illustrating their cellular and molecular signaling processes initiated by HIMF and elucidating the underlying mechanism. The three related specific aims are directed at understanding: (1) the roles of HIMF in mediating the intracellular and extracellular activity and the epigenetic modification of DAMP molecules; (2) the downstream events of the HIMF/DAMP signaling axis, including autophagy/apoptosis regulation, BMPR2 and FoxO1 downregulation and their possible interaction; and (3) the expression/production of DAMPs and their downstream mediators in PH development, as well as the correlation of these molecules in existing clinical PH patient specimens. The goal of this proposal is to further clarify the relation between the immunomodulatory properties of HIMF and the etiology of PH, and thereby to explore a novel therapeutic approach for PH and other vascular inflammation-related diseases.

总结 缺氧诱导的促有丝分裂因子（HIMF;也称为FIZZ 1或抵抗素样分子）对 肺动脉高压（PH）的发展在啮齿动物模型，我们的工作表明，HIMF可能会触发一个 正反馈回路放大血管重塑所需的炎症。我们认为 HIMF人类同源物，人类特发性和硬皮病相关PH中的人类HIMF蛋白（hIMF蛋白）。 对啮齿动物和人类PH至关重要的下游血管和免疫过程被HIMF激活， 但HIMF/hmpn以病理方式启动这些反应的方式仍然存在 未知损伤相关分子模式分子（DAMPs），包括高迁移率族蛋白 （HMGB）1和S100钙结合蛋白，作为内源性危险信号调节随后的 炎症反应通过自分泌和旁分泌的方式通过激活受体的先进 糖基化终产物（glycation end-products，GST）。我们现在显示HIMF和hresistin诱导的HMGB 1和S100 A11激活， 与PH相关的人血管和免疫细胞以及PH动物模型。然而， HIMF/hmpn对这种反应的调节以及HIMF/DAMP/Hmpn信号轴在PH期间的功能 发展仍不明朗。在初步研究中，我们发现HIMF信号转导激活HMGB 1/HMGB 2， 轴在体内和体外与抑制sirtuin（Sirt）1，增强自噬，减弱 叉头盒O（FoxO）1和骨形态发生蛋白受体（BMPR）2的表达，以及高表达 肺动脉平滑肌细胞（PASMC）增殖。此外，在我们的初步研究中， DAMP，S100 A11，也被发现在PH患者的外周血单核细胞中增加。 在这个提议中，我们假设HIMF/hmpn激活的DAMP信号传导介导了交叉- 血管细胞和免疫细胞之间的对话，启动自噬反应，并下调 FoxO 1和BMPR 2，从而有助于PH的病理生理学。我们将研究DAMP的作用 通过说明其在HIMF诱导的炎症反应和随后的血管重塑中的作用 由HIMF启动的细胞和分子信号传导过程，并阐明了 机制三个相关的具体目标是为了理解：（1）HIMF在 介导DAMP分子的细胞内和细胞外活性和表观遗传修饰;（2） HIMF/DAMP信号传导轴的下游事件，包括自噬/凋亡调节、BMPR 2和 FoxO 1下调及其可能的相互作用;和（3）DAMP及其表达/产生 PH发展中的下游介质，以及这些分子在现有临床PH中的相关性 患者标本。该提案的目的是进一步阐明免疫调节与免疫抑制之间的关系。 HIMF的性质和PH的病因，从而探索一种新的治疗PH的方法， 其他血管炎症相关疾病。