High-mobility group box-1 induces vascular remodelling processes via c-Jun activation

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Molecular Biology

Background:

• Extracellular high-mobility group box-1 (HMGB1) is a signaling molecule implicated in inflammation, cell differentiation, and angiogenesis.
• Elevated HMGB1 levels are associated with various pathological conditions, including cancer, asthma, and chronic obstructive pulmonary disease (COPD).

Purpose of the Study:

• To investigate the role of HMGB1 in the pathological vascular remodeling observed in idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension (PH) associated with COPD.
• To explore the cellular mechanisms by which HMGB1 contributes to vascular remodeling in PH.

Main Methods:

• Analysis of HMGB1-positive cell infiltration in lung tissues from IPAH and COPD with PH patients.
• Quantification of serum HMGB1 levels in patient cohorts and controls.
• In vitro experiments assessing the effects of HMGB1 on pulmonary arterial smooth muscle cells (PASMC) and primary human arterial endothelial cells (PAEC) proliferation and signaling pathways.
• Gene silencing of c-Jun to evaluate its role in HMGB1-induced proliferation.

Main Results:

• HMGB1-positive cells were frequently observed surrounding remodeled vessels in IPAH and COPD with PH lung samples.
• Serum HMGB1 levels were significantly elevated in both patient groups compared to controls.
• HMGB1 enhanced PASMC and PAEC proliferation in vitro.
• HMGB1 stimulated phosphorylation of p38, ERK, and JNK kinases, leading to AP-1 complex activation (c-Fos and c-Jun).
• Silencing c-Jun abolished HMGB1-induced PASMC proliferation.

Conclusions:

• HMGB1 is implicated in the vascular remodeling characteristic of IPAH and COPD-associated PH.
• HMGB1 promotes proliferation of pulmonary arterial smooth muscle cells and endothelial cells through activation of MAPK/AP-1 signaling pathways.
• HMGB1 represents a potential therapeutic target for mitigating vascular remodeling and pathogenesis in pulmonary hypertension.