HMGB1 protein interacting with pulmonary arteries.

Unlocking the Mystery of Pulmonary Hypertension: How HMGB1 Holds the Key

Author's portrait.
Beau Callahan in Health & Wellness August 2025 • 4 min read.

"New research reveals the critical role of HMGB1 in the development of pulmonary hypertension, offering potential new targets for treatment and prevention."


Pulmonary hypertension (PH) is a devastating disease characterized by the narrowing of pulmonary arteries, leading to right heart failure and ultimately, death. While the exact causes of PH remain elusive, inflammation and the mobilization of intracellular calcium are known contributors. High-mobility group box 1 (HMGB1), a DNA chaperone with diverse cellular functions, has recently emerged as a critical player in PH development.

HMGB1, traditionally known for its role in DNA repair and replication within the cell nucleus, takes on a different persona when it ventures outside. Released into the cytoplasm or extracellular space, HMGB1 acts as a damage-associated molecular pattern (DAMP), triggering a cascade of cellular responses, including inflammation and immunity. This dual nature of HMGB1 has sparked intense research into its role in various diseases, including pulmonary hypertension.

Recent studies have highlighted HMGB1's involvement in PH, with researchers exploring its potential as a therapeutic target. Now, a groundbreaking study sheds new light on the mechanistic importance of HMGB1 in pulmonary hypertension, revealing its intricate interplay with toll-like receptor 4 (TLR4), calcium signaling, and the Akt pathway. This discovery paves the way for novel strategies to combat this life-threatening condition.

How Does HMGB1 Contribute to Pulmonary Hypertension?

HMGB1 protein interacting with pulmonary arteries.

The new research paper uncovers a cascade of events initiated by HMGB1 that leads to the progression of pulmonary hypertension. The study, conducted on rat models, reveals that HMGB1 levels surge in lung tissue and blood plasma following chronic hypoxia exposure and monocrotaline treatment, two common methods for inducing PH in animals. This surge prompts HMGB1 to translocate from the nucleus to the cytoplasm in pulmonary artery smooth muscle cells (PASMCs), a process seemingly mediated by the production of reactive oxygen species (ROS).

Once in the cytoplasm, HMGB1 mobilizes calcium signaling in PASMCs, setting off a chain reaction that promotes constriction and remodeling of the pulmonary arteries. This calcium signaling is attenuated by the removal of extracellular calcium, inhibition of TLR4 (a receptor that binds HMGB1), or suppression of transient receptor potential channels (TRPC), key players in calcium influx.

  • HMGB1 Release: Increased levels of HMGB1 are observed in lung tissue and blood plasma under PH-inducing conditions.
  • Cellular Translocation: HMGB1 moves from the nucleus to the cytoplasm in PASMCs.
  • Calcium Mobilization: HMGB1 triggers calcium signaling within PASMCs.
  • TLR4 and TRPC Involvement: This signaling is dependent on TLR4 and TRPC channels.
The study further demonstrates that the Akt pathway, a critical regulator of cell growth and survival, is also activated by HMGB1. The sustained phosphorylation of Akt modulates HMGB1-induced migration of PASMCs, contributing to the vascular remodeling characteristic of PH. Blocking HMGB1 with glycyrrhizin or a neutralizing antibody effectively mitigates lung inflammation and PH establishment in the rat models.

Implications for Future Therapies

These findings highlight the mechanistic importance of HMGB1 in pulmonary hypertension. By revealing its role in TLR4- and TRPC-associated calcium influx, and Akt phosphorylation-driven PASMC migration, this research identifies potential new targets for therapeutic intervention. Future research efforts should focus on developing HMGB1 inhibitors or strategies to disrupt its interaction with TLR4 and downstream signaling pathways. This could pave the way for more effective treatments for pulmonary hypertension.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1152/ajpcell.00148.2018, Alternate LINK

Title: Hmgb1 Is Mechanistically Essential In The Development Of Experimental Pulmonary Hypertension

Subject: Cell Biology

Journal: American Journal of Physiology-Cell Physiology

Publisher: American Physiological Society

Authors: Mao Dai, Rui Xiao, Luyao Cai, Tong Ge, Liping Zhu, Qinghua Hu

Published: 2019-02-01

Everything You Need To Know

1

What is pulmonary hypertension, and why is it a concern?

Pulmonary hypertension (PH) is a serious condition characterized by high blood pressure in the lungs, which leads to right heart failure and ultimately, death. The narrowing of pulmonary arteries is a key feature of PH. The article details the crucial role of HMGB1 in the development of this condition, making it a central focus of research into potential therapies.

2

What is HMGB1 and what are its main functions?

HMGB1, or High-mobility group box 1, is a protein that, inside the cell nucleus, is involved in DNA repair and replication. However, when released into the cytoplasm or extracellular space, HMGB1 acts as a damage-associated molecular pattern (DAMP), triggering inflammation and immune responses. This dual nature is critical to understanding its role in various diseases, including pulmonary hypertension (PH).

3

How does HMGB1 contribute to pulmonary hypertension?

HMGB1 contributes to pulmonary hypertension through a cascade of events. First, its levels increase in lung tissue and blood plasma. Then, HMGB1 moves from the nucleus to the cytoplasm in pulmonary artery smooth muscle cells (PASMCs). Once in the cytoplasm, HMGB1 mobilizes calcium signaling within PASMCs, promoting constriction and remodeling of pulmonary arteries. This process is dependent on TLR4 and TRPC channels. Additionally, HMGB1 activates the Akt pathway, influencing the migration of PASMCs and contributing to vascular remodeling.

4

What is the role of TLR4 and TRPC channels in the context of HMGB1 and pulmonary hypertension?

TLR4, or toll-like receptor 4, is a receptor that binds HMGB1. The research indicates that HMGB1's effects on calcium signaling, leading to the progression of pulmonary hypertension, are dependent on the presence of TLR4 and TRPC channels. Blocking TLR4 or suppressing TRPC channels can lessen the effects of HMGB1, suggesting potential therapeutic targets.

5

What are the implications of this research for future treatments of pulmonary hypertension?

These findings suggest that future therapies could focus on inhibiting HMGB1 or disrupting its interaction with TLR4 and downstream signaling pathways. Specifically, targeting the Akt pathway and the calcium signaling cascade offer new opportunities for treatment. The use of HMGB1 inhibitors or neutralizing antibodies has shown promise in mitigating lung inflammation and preventing the establishment of PH in animal models.

Newsletter Subscribe

Subscribe to get the latest articles and insights directly in your inbox.