# DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $454,909

## Abstract

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
...

## Key facts

- **NIH application ID:** 9976575
- **Project number:** 5R01HL138497-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Roger A Johns
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,909
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976575

## Citation

> US National Institutes of Health, RePORTER application 9976575, DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension (5R01HL138497-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976575. Licensed CC0.

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