Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats - PubMed (original) (raw)
Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats
Pil-Sung Yang et al. Respir Res. 2014.
Erratum in
- Erratum to: Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats.
Yang PS, Kim DH, Lee YJ, Lee SE, Kang WJ, Chang HJ, Shin JS. Yang PS, et al. Respir Res. 2016 Nov 4;17(1):142. doi: 10.1186/s12931-016-0458-9. Respir Res. 2016. PMID: 27814697 Free PMC article. No abstract available.
Abstract
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.
Figures
Figure 1
Scheme of animal experimental timeline. Pulmonary hypertension was induced by a single subcutaneous injection of MCT (60 mg/kg). The GLY (50 mg/k) was intraperitoneally treated once daily immediately after MCT injection for 4 weeks or 6 weeks in the MCT + GLY group, while normal saline was injected in the MCT group. Hemodynamic changes, RV hypertrophy, histological changes of lung, micro-PET, and survival rate were measured at the end of the animal experiment.
Figure 2
Increased tissue and serum levels of HMGB1 in pulmonary hypertension rats induced by MCT. A–C: Lung sections of normal control rats. D–F: Lung sections of MCT-induced pulmonary hypertension rats at day 28 after MCT injection. A, D: Hematoxylin and eosin staining. B, C, E, F: Immunohistochemical staining with anti-HMGB1 antibody (brown). (A) No inflammatory cell was observed in the lungs of normal control rats. (B, C) HMGB1 was mainly localized to the nucleus (black arrow). (D) A large number of inflammatory cells (white arrow) were recruited to the lungs of MCT-induced pulmonary hypertension rats. (E, F) HMGB1 translocated to the extranuclear area (triangle). (G) The proportion of cytoplasmic HMGB1 positive cells in lung tissue of MCT-induced pulmonary hypertension rats was greater than in that of normal control rats (*p <0.001). (H) Serum levels of HMGB1 in MCT-injected rats increased significantly 2 weeks after the MCT injection and remained elevated (*p <0.001 when compared to initial serum level of HMGB1). Data are presented as means ± SEM (n =10).
Figure 3
Expression pattern of HMGB1 in the pulmonary vascular lesion. Immunohistochemical staining with anti-HMGB1 antibody (brown color) and counterstaining with hematoxylin was performed on lung tissues of normal control rats and MCT-induced pulmonary hypertension rats at day 28 after MCT injection. A, C: Sections of large arteries. B, D: Sections of small vessels of lung tissue. (A, B) In normal control rats, HMGB1 was present only in the nuclei of smooth muscle cells (black arrow) and endothelial cells (black triangle). (C, D) However, in MCT-induced pulmonary hypertension rats, HMGB1 was present in both the nuclei and cytoplasm of smooth muscle cells (white arrow) and endothelial cells (white triangle). There were many inflammatory cells around the vessels with cytoplasmic HMGB1 translocation in MCT-induced pulmonary hypertension rats (white asterisk).
Figure 4
Inhibition of HMGB1 by GLY treatment attenuated the MCT-induced increase of RV systolic pressure and RV hypertrophy. (A) MCT-injected rats exhibited increased RVSP when compared with control rats (*p = 0.002). GLY treatment reduced the MCT-induced increase of RVSP (†p = 0.045 when compared to the MCT group treated for 4 weeks; ‡p = 0.002 when compared to the MCT group treated for 6 weeks). GLY treated alone without MCT yielded no significant difference in RVSP when compared with that of control rats (p = 0.307). (B) RV hypertrophy (RV/(LV + S)) increased significantly in the MCT group when compared with the control group (**p <0.001). GLY treatment reduced the MCT-induced increase of RV hypertrophy, although only rats given a 6-week GLY treatment course exhibited a statistically significant difference (††p = 0.418 when compared with the MCT group treated for 4 weeks; ‡‡p = 0.002 when compared with the MCT group treated for 6 weeks). GLY treated alone without MCT yielded no significant difference in RV hypertrophy when compared with that of controls (p =0.656). Data are presented as means ± SEM.
Figure 5
MCT-induced increases in both medial wall thickness and muscularization of pulmonary arteries were attenuated through the HMGB1 inhibition by GLY treatment. (A, B) Elastica-eosin staining showing that the medial area between the lamina elastica interna and externa (deep violet) increased in the MCT group when compared with the normal control group (*p <0.001). Treatment with GLY attenuated the medial change induced by MCT injection (†p <0.001). GLY treated alone without MCT yielded no significant difference in medial wall thickness when compared with that of control rats (p = 0.501). (C, D) The degree of muscularization of pulmonary arteries was observed via immunostaining of α-SMA (brown) and vWF (purple). In the MCT group, the proportion of muscularized pulmonary arteries increased when compared with the control group (■p <0.001). GLY treatment attenuated this MCT-induced muscularization of pulmonary arteries (♦p <0.001). GLY treated alone without MCT yielded no significant difference in pulmonary artery muscularization when compared with that of control rats (p = 0.262). Data are presented as means ± SEM.
Figure 6
Effect of GLY treatment on survival rate and pulmonary inflammation in the MCT-induced pulmonary hypertension rat. (A) GLY was administered for 42 days, and rat survival was compared with the non-treated MCT group. The survival rate was 60% in the non-treated MCT group; in contrast, the survival rate was 90% in the MCT + GLY group (*p = 0.0027). (B, C) The degree of pulmonary inflammation was measured by micro-PET at 28 days post-MCT injection. The SUV of the lung field increased in the MCT group compared with the control group (*p = 0.009). GLY treatment reduced the SUV of the lung field when compared with that of the non-treated MCT group (†p = 0.018). Data are presented as means ± SEM.
Figure 7
HMGB1 induced ET-1 release from HPAECs and proliferation of HPASMCs. (A) HMGB1-stimulated ET-1 release from HPAECs. Release of ET-1 was approximately 10% higher in the HMGB1-treated (40 ng/ml) group than in the control group (*p <0.001). (B, C) ET-1 release from HPAECs was attenuated by treatment antibodies against HMGB1 or RAGE in a dose-dependent manner (†p = 0.011; ‡p = 0.006). (D) HPASMCs were cultured with serum-free medium alone or 10% FBS, or in the presence of 30 ng/ml HMGB1. HMGB1 induced proliferation of HPASMCs (p <0.001). Data are presented as means ± SEM.
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