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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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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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Fig7: 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.

Mentions: To determine whether HMGB1 plays a role in endothelial hyperactivity in pulmonary hypertension, we quantified ET-1 release from cultured HPAECs after stimulation with HMGB1. Release of ET-1 was higher in the HMGB1-treated (40 ng/ml) group (109.7%; 381.92 ± 7.1 pg/ml) than in the non-treated control group (348.23 ± 12.2 pg/ml; p <0.001) (Figure 7A). Furthermore, HMGB1 increased the release of ET-1 from HPAECs in a dose-dependent manner (range, 10–40 ng/ml). Moreover, the addition of antibodies against HMGB1 (1 μg/ml) significantly attenuated HMGB1-induced ET-1 release (at 40 ng/ml HMGB1) from 384.16 ± 1.3 pg/ml to 359.63 ± 5.1 pg/ml (p = 0.011) (Figure 7B). Likewise, anti-RAGE antibodies (1 μg/ml) also reduced the amount of HMGB1-induced ET-1 release from 381.56 ± 17.3 pg/ml to 348.51 ± 16.3 pg/ml (p = 0.006) (Figure 7C).Figure 7


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)

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

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Fig7: 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.
Mentions: To determine whether HMGB1 plays a role in endothelial hyperactivity in pulmonary hypertension, we quantified ET-1 release from cultured HPAECs after stimulation with HMGB1. Release of ET-1 was higher in the HMGB1-treated (40 ng/ml) group (109.7%; 381.92 ± 7.1 pg/ml) than in the non-treated control group (348.23 ± 12.2 pg/ml; p <0.001) (Figure 7A). Furthermore, HMGB1 increased the release of ET-1 from HPAECs in a dose-dependent manner (range, 10–40 ng/ml). Moreover, the addition of antibodies against HMGB1 (1 μg/ml) significantly attenuated HMGB1-induced ET-1 release (at 40 ng/ml HMGB1) from 384.16 ± 1.3 pg/ml to 359.63 ± 5.1 pg/ml (p = 0.011) (Figure 7B). Likewise, anti-RAGE antibodies (1 μg/ml) also reduced the amount of HMGB1-induced ET-1 release from 381.56 ± 17.3 pg/ml to 348.51 ± 16.3 pg/ml (p = 0.006) (Figure 7C).Figure 7

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