Journal Article

Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats

Lee, Sang-Eun, Kim, Dae-Hoon, Shin, Jeon-Soo, Kang, Won Jun, Lee, Yong Joon, Chang, Hyuk-Jae, Yang, Pil-Sung

2014

Overview

Background High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT). Methods After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague–Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks. Results Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027). Conclusions Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group
• Subject: Angiogenesis / Animal diseases / Animal models / Animals / Antibodies / Antihypertensive Agents - pharmacology / Arterial Pressure - drug effects / Attenuation / Blood pressure / Cell Proliferation - drug effects / Cells, Cultured / Complications and side effects / Disease / Disease Models, Animal / Disease progression / Dose-Response Relationship, Drug / Drug dosages / Drug therapy / Endothelin-1 - metabolism / Experiments / Genetic aspects / Glycyrrhizic Acid - pharmacology / Glycyrrhizin / Heart / Hemodynamics / HMGB1 protein / HMGB1 Protein - antagonists & inhibitors / HMGB1 Protein - metabolism / Humans / Hypertension / Hypertension, Pulmonary - chemically induced / Hypertension, Pulmonary - metabolism / Hypertension, Pulmonary - pathology / Hypertension, Pulmonary - physiopathology / Hypertension, Pulmonary - prevention & control / Hypertrophy / Hypertrophy, Right Ventricular - metabolism / Hypertrophy, Right Ventricular - physiopathology / Hypertrophy, Right Ventricular - prevention & control / Inflammation / Inhibitors / Injection / Laboratory animals / Lungs / Male / Medical research / Medicine / Medicine & Public Health / Microscopy / Monocrotaline / Mortality / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - pathology / Pathogenesis / Physiological aspects / Pneumology/Respiratory System / Pneumonia - metabolism / Pneumonia - physiopathology / Pneumonia - prevention & control / Pulmonary arteries / Pulmonary artery / Pulmonary Artery - drug effects / Pulmonary Artery - metabolism / Pulmonary Artery - pathology / Pulmonary Artery - physiopathology / Pulmonary hypertension / Rats, Sprague-Dawley / Rodents / Smooth muscle / Studies / Systolic pressure / Therapeutic targets / Time Factors / University colleges / Vascular Remodeling - drug effects / Veins & arteries / Ventricular Dysfunction, Right - metabolism / Ventricular Dysfunction, Right - physiopathology / Ventricular Dysfunction, Right - prevention & control / Ventricular Function, Right - drug effects