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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 - Respir. Res. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, 50 Yonsei-ro Seodaemun-gu, Seoul, 120-752, Republic of Korea. psyang@yuhs.ac.

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.

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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.
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Fig1: 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.

Mentions: This animal study protocol was approved by Institutional Animal Care and Use Committee of Yonsei University Health System, in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, USA). We performed animal experiments twice, for 4-week and 6-week periods, to evaluate both the established stage and the end stage of pulmonary hypertension. Male Sprague–Dawley rats (body weight 240–260 g) were randomly divided into 3 groups in each experiment: Group 1, initially given a single subcutaneous injection of normal saline and no treatment (control group; n = 5 [4 weeks] and 10 [6 weeks]); Group 2, initially given a single subcutaneous injection of MCT (0.5 ml, 60 mg/kg; c2401; Sigma-Aldrich) and once daily intraperitoneal treatment of normal saline (MCT group; n = 10 [4 weeks] and 20 [6 weeks]); and Group 3, initially given a single subcutaneous injection of MCT (0.5 ml, 60 mg/kg) and once daily intraperitoneal treatment of glycyrrhizin (GLY) (50 mg/kg; 50531; Sigma-Aldrich) (MCT + GLY group; n = 10 [4 weeks] and 20 [6 weeks]). After the above animal experiments, an additional experiment was performed to verify the effects of GLY alone without MCT on the pulmonary vascular system. An initial single subcutaneous injection of normal saline and once daily intraperitoneal treatment of GLY (50 mg/kg) for 4 weeks was performed in male Sprague–Dawley rats (GLY group; n = 6). The MCT was dissolved in 1.0 N HCl, and the pH was adjusted to 7.4 with 0.5 N NaOH. A dose of 50 mg/kg GLY was selected on the basis of previous animal studies using GLY [21,22]. A timeline of the animal experiments is illustrated in Figure 1.Figure 1


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 - Respir. Res. (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4248446&req=5

Fig1: 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.
Mentions: This animal study protocol was approved by Institutional Animal Care and Use Committee of Yonsei University Health System, in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, USA). We performed animal experiments twice, for 4-week and 6-week periods, to evaluate both the established stage and the end stage of pulmonary hypertension. Male Sprague–Dawley rats (body weight 240–260 g) were randomly divided into 3 groups in each experiment: Group 1, initially given a single subcutaneous injection of normal saline and no treatment (control group; n = 5 [4 weeks] and 10 [6 weeks]); Group 2, initially given a single subcutaneous injection of MCT (0.5 ml, 60 mg/kg; c2401; Sigma-Aldrich) and once daily intraperitoneal treatment of normal saline (MCT group; n = 10 [4 weeks] and 20 [6 weeks]); and Group 3, initially given a single subcutaneous injection of MCT (0.5 ml, 60 mg/kg) and once daily intraperitoneal treatment of glycyrrhizin (GLY) (50 mg/kg; 50531; Sigma-Aldrich) (MCT + GLY group; n = 10 [4 weeks] and 20 [6 weeks]). After the above animal experiments, an additional experiment was performed to verify the effects of GLY alone without MCT on the pulmonary vascular system. An initial single subcutaneous injection of normal saline and once daily intraperitoneal treatment of GLY (50 mg/kg) for 4 weeks was performed in male Sprague–Dawley rats (GLY group; n = 6). The MCT was dissolved in 1.0 N HCl, and the pH was adjusted to 7.4 with 0.5 N NaOH. A dose of 50 mg/kg GLY was selected on the basis of previous animal studies using GLY [21,22]. A timeline of the animal experiments is illustrated in Figure 1.Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, 50 Yonsei-ro Seodaemun-gu, Seoul, 120-752, Republic of Korea. psyang@yuhs.ac.

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.

Show MeSH
Related in: MedlinePlus