Abstract 16928: Inhibition of Pro-Inflammatory Cytokine HMGB1 Attenuate Disease Progression of Pulmonary Arterial Hypertension in Rats
Background: — The inflammatory process plays a pivotal role in various types of vasculopathy. HMGB1, pro-inflammatory cytokine, has been known to involve in the process of tissue remodeling and angiogenesis, which are crucial steps in the pathogenesis of pulmonary arterial hypertension (PAH). In this study, we explored whether the inhibition of HMGB1 attenuates disease progression of PAH in the animal model.
Methods and Results: — PAH was induced by monocrotaline (MCT: 60mg/kg, single bolus, SQ) in Sprague-Dawley rats. HMGB1 inhibitor (glycyrrhizin (Gly): 50mg/kg), or normal saline (NS) were administered daily by the intraperitoneal route. After 4 and 6 weeks treatments, PET imaging, hemodynamic study, and histological analysis were performed. Serum HMGB1 levels started to increase significantly after 2 weeks of MCT injection (from 2.17 ± 0.81 to 4.61 ± 1.2 ng/ml, p<0.05). Chronic inhibition of HMGB1 for 4 weeks by Gly reduced MCT-induced increase in right ventricular (RV) systolic pressure (58.5 ± 21.7 vs. 39.2 ± 8.5 mmHg, p<0.05) and RV hypertrophy (RV free wall / [LV + Septum]: 0.62 ± 0.03 vs. 0.51 ± 0.08, p<0.05). Also, MCT-induced muscularization and medial thickening of pulmonary artery were reduced by Gly treatment. Furthermore, Gly treatment for 6 weeks resulted in survival benefit (90% [18 of 20] vs. 60% [12 of 20], p<0.05).
Conclusion: — Chronic inhibition of HMGB1 can attenuate progression of PAH and pulmonary vascular remodeling in MCT-treated rats. It could be a new therapeutic target in PAH.
- © 2010 by American Heart Association, Inc.