# HMGBG1 and Gender Difference in Pulmonary Arterial Hypertension

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $383,750

## Abstract

Title: HMGB1 and gender difference in pulmonary arterial hypertension
Abstract: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased
pulmonary vascular resistance (PVR) and right ventricle (RV) hypertrophy. Despite recent
progress, there is still inadequate treatment for this disease, with medial survival for the patients
with Functional Class III and IV as low as 2.5 years and 6 months.
There is a well-established sexual dimorphism in regard to PAH, especially idiopathic PAH, with
females generally being associated with higher susceptibility to PAH, while males possessing
lower survival rate and predisposition to develop RV failure. Our recently published research
highlights two distinct gender-associated phenotypes of PAH: an excessive level of pulmonary
vascular remodeling associated with the female gender, and an inflammation of pulmonary
vascular wall and RV fibrosis in males.
The pro-inflammatory signaling has been inextricably linked to initiation and progression of PAH.
High mobility group box 1 (HMGB1) is a nuclear factor released during cell death that stimulates
immune cell activation via p PRR), including toll-like receptor 4
(TLR4) and the receptor for advanced glycation endproducts (RAGE). TLR4 activation
increases pro-inflammatory immune cell activation. In contrast, RAGE, while involved in
inflammation, can limit an immune response and activate pro-surviving process.
A recent publication reveals that males and females are prone to different types of the cell death
in response to initial damage, with male cells more likely to die by necrosis, and females – by
apoptosis. As HMGB1 needs to be in a reduced state to bind to TLR4, we hypothesize that the
reduced environment created by necrotic cell death promotes HMGB1 mediated TLR4
activation and inflammation in males, while in females, apoptotic cells release HMGB1 in
oxidized state, leading to activation of RAGE and proliferative response.
e have designed peptides to selectively inhibit necrosis-mediated TLR4 activation or the
apoptosis-mediated RAGE activation by prevention of their interaction with HMGB1. We will
further investigate the therapeutic potential of these peptides by testing them in a rodent model
of PAH for the ability to inhibit TLR4 or RAGE and, thus, evaluate the particular contribution of
these pathways in PAH of either sex.
attern recognition receptors (
W

## Key facts

- **NIH application ID:** 9963375
- **Project number:** 5R01HL133085-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Olga Rafikova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963375

## Citation

> US National Institutes of Health, RePORTER application 9963375, HMGBG1 and Gender Difference in Pulmonary Arterial Hypertension (5R01HL133085-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963375. Licensed CC0.

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