DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

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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.