DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

摘要 低氧诱导的有丝分裂因子(HIMF；也称为FIZZ1或抵抗素样分子-)在 在啮齿动物模型中发生肺动脉高压，我们的工作表明，HIMF可能触发了 正反馈环，放大重塑所需的血管炎症。我们已经牵连到 人类特发性和硬皮病相关的PH中的人类HIMF、人类抵抗素(HResistn)同源物。几个 Himf和Himf激活对啮齿动物和人类PH至关重要的下游血管和免疫过程 但HIMF/HResitn以病理性方式启动这些反应的方式仍然存在 未知。损伤相关分子图案分子(DAMP)，包括高迁移率基团框 (HMGB)1和S100钙结合蛋白作为内源性危险信号调节随后的 通过激活晚期受体的自分泌和旁分泌方式的炎症反应 糖基化终产物(RAGE)。我们现在展示了Himf和hResistn诱导的HMGB1和S100A11在 人类血管和免疫细胞与肺高压相关，以及在肺高压动物模型中。然而，它的作用机制 Himf/hResistn对这一反应的调节以及Himf/DAMP/RAGE信号轴在PH中的作用 事态发展仍不明朗。在初步研究中，我们发现Himf信号激活了HMGB1/RAGE AXIS在体内和体外与抑制的sirtuin(Sirt)1相关，增强的自噬，减弱 叉头盒O(FoxO)1和骨形态发生蛋白受体(BMPR)2的表达 PASMC的增殖情况。此外，在我们的初步研究中，另一项 DAMP，S100A11，也被发现在PH患者的外周血单核细胞中增加。 在这一建议中，我们假设Himf/hResitin激活的DAMP信号介导了交叉反应。 血管细胞和免疫细胞之间的对话，启动自噬反应，并下调 Foxo1和BMPR2，从而参与了PH的病理生理过程。我们将研究阻尼器的作用 在HIMF诱导的炎症反应和随后的血管重塑中 由HIF启动的细胞和分子信号传递过程及其潜在的 机制。三个相关的具体目的是为了理解：(1)他在 介导细胞内外活性和DAMP分子的表观遗传修饰；(2) HIMF/DAMP信号轴的下游事件，包括自噬/凋亡调节，BMPR2和 Foxo1下调及其可能的相互作用；以及(3)DAMP及其受体的表达/产生 肺高压发生中的下游介质以及这些分子在现有的临床肺高压中的相关性 病人样本。这项建议的目的是进一步澄清免疫调节与 HIF的特性和PH的病因，从而探索一种新的治疗PH和 其他与血管炎症相关的疾病。

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.