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Exendin-4 inhibits HMGB1-induced inflammatory responses in HUVECs and in murine polymicrobial sepsis
Wonhwa Lee1, Sae-Kwang Ku, Eun Ji Park
1College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 702-701, Republic of Korea.
Abstract:
Exendin-4 (EX4) has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury and inflammatory and oxidative responses. Nuclear DNA-binding protein high-mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. However, the effect of EX4 on HMGB1-induced inflammatory response has not been studied. First, we accessed this question by monitoring the effects of posttreatment EX4 on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Posttreatment EX4 was found to suppress LPS-mediated release of HMGB1 and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. EX4 also induced downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that EX4 may be regarded as a candidate therapeutic agent for treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.
Insights
Exendin-4 (EX4) treatment reduces high-mobility group box 1 (HMGB1) release and inflammatory responses in sepsis models. This suggests EX4 is a potential therapy for vascular inflammation by inhibiting HMGB1 signaling.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Endothelial Cell Biology
Background:
- Exendin-4 (EX4) is known to reduce myocardial ischemia-reperfusion injury and associated inflammatory/oxidative stress.
- High-mobility group box 1 (HMGB1) protein is implicated as a key mediator in severe vascular inflammatory conditions.
- The specific impact of EX4 on HMGB1-induced inflammatory responses remains largely uninvestigated.
Purpose of the Study:
- To investigate the therapeutic potential of Exendin-4 (EX4) in modulating High-mobility group box 1 (HMGB1)-induced inflammatory responses.
- To determine the effect of EX4 post-treatment on HMGB1 release and downstream inflammatory pathways in both in vitro and in vivo models of inflammation.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) and septic mouse models were utilized.
- Lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) were employed to induce inflammatory responses and HMGB1 release.
- The effects of EX4 post-treatment on HMGB1 levels, vascular hyperpermeability, leukocyte migration, IL-6 production, and mortality were assessed.
Main Results:
- Post-treatment with EX4 significantly suppressed LPS-induced HMGB1 release in HUVECs.
- In septic mice, EX4 administration inhibited HMGB1-mediated hyperpermeability and leukocyte migration.
- EX4 treatment led to reduced CLP-induced HMGB1 release, decreased IL-6 production, and lowered mortality rates.
Conclusions:
- Exendin-4 (EX4) demonstrates a significant role in attenuating HMGB1-mediated inflammatory responses.
- EX4 effectively suppresses key inflammatory mediators and improves survival in sepsis models.
- These findings position EX4 as a promising therapeutic candidate for vascular inflammatory diseases through the inhibition of the HMGB1 signaling pathway.
