黄芩苷通过抑制血管重构对实验性肺动脉高压的治疗作用研究

doi:10.5246/jcps.2020.10.067

中国药学(英文版) ›› 2020, Vol. 29 ›› Issue (10): 719-728.DOI: 10.5246/jcps.2020.10.067

黄芩苷通过抑制血管重构对实验性肺动脉高压的治疗作用研究

蒋雯, 孙超, 王珏, 辛倩, 李开霖, 亓同钢, 栾云^*

山东大学齐鲁医学院, 基础医学研究所中心实验室, 山东济南 250000

收稿日期:2020-06-17 修回日期:2020-07-21 出版日期:2020-10-31 发布日期:2020-09-14
通讯作者: Tel.: +86-15064012955, E-mail: luanyun@sdu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81500042), the Science and Technology Development Project of Jinan Medical and Health (Grant No. 201907040), the Science and Technology Development Project of Shandong Province (Grant No. 2019GSF107093), and Youth Interdisciplinary Innovation Science Fund of Shandong University (Grant No. 2020QNQT019).

Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling

Wen Jiang, Chao Sun, Jue Wang, Qian Xin, Kailin Li, Tonggang Qi, Yun Luan^*

Central Research Laboratory, Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250000, China

Received:2020-06-17 Revised:2020-07-21 Online:2020-10-31 Published:2020-09-14
Contact: Tel.: +86-15064012955, E-mail: luanyun@sdu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81500042), the Science and Technology Development Project of Jinan Medical and Health (Grant No. 201907040), the Science and Technology Development Project of Shandong Province (Grant No. 2019GSF107093), and Youth Interdisciplinary Innovation Science Fund of Shandong University (Grant No. 2020QNQT019).

摘要/Abstract

摘要：

文献报道黄芩苷对肺动脉高压与右心室肥大具有抑制作用, 但是作用机制尚不明确。最新研究显示, NF-κB与BMP信号通路在PAH中具有重要作用, NF-κB-BMP信号轴已经成为研究肺动脉高压血管重构发病机制的重要靶点。本研究目的是观察黄芩苷对实验性肺动脉高压血管重构的抑制作用以及对NF-κB-BMP信号轴的调控作用。结果显示黄芩苷能明显降低野百合诱导的肺动脉高压右心室收缩压与右心室肥厚指数, 抑制肺动脉高压血管重构(P < 0.05)。利用Western blot进行蛋白检测, 结果显示BMPR2蛋白表达明显提高, 而NF-κB p65、p-NF-κB p65、I-κBα与BMP抑制剂gremlin 1明显降低(P < 0.05); 免疫组织化学结果显示肺血管密度明显提高(P < 0.05)。以上实验结果说明, 黄芩苷对肺动脉高压肺脏和心脏损伤具有抑制作用是通过调控NF-κB-BMP信号通路, 这将为防治肺动脉高压提供新的思路与方法。

关键词: 黄芩苷, 肺动脉高压, 血管重构, NF-κB, BMP

Abstract:

Previous studies have shown that baicalin can attenuate pulmonary arterial hypertension and right ventricular hypertrophy. However, the potential mechanism remains unexplored. Nuclear factor-κB (NF-κB) and bone morphogenetic protein (BMP) signaling pathway play an important role in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). Therefore, we aimed to observe the regulation of baicalin on the NF-κB-BMP axis and the subsequent anti-proliferation in pulmonary vascular. Our results showed that baicalin could significantly decrease right ventricular systolic pressure (RVSP) and the RV/left ventricle plus septum ratio (P < 0.05), and attenuate vascular remodeling. Furthermore, the result of westen blot showed that the protein expression level of BMP receptor 2 (BMPR2) was significantly increased, while NF-κB p65, p-NF-κB p65, inhibitor of NF-κB (I-κBα) and the BMP antagonist, gremlin 1 were significantly down-regulated in the baicalin group (P < 0.05). On the other hand, the result of immunohistochemical staining in lung showed that the capillary density of pulmonary arterioles significantly increased in the baicalin group compared with the MCT group (P < 0.05). We concluded that baicalin exerted the protective effects against the lung and heart damage through inhibiting NF-κB-BMP signaling pathway, providing new mechanistic information about PAH and right ventricular hypertrophy.

Key words: Baicalin, Pulmonary arterial hypertension, Pulmonary vascular remodeling, NF-κB, BMP

中图分类号:

R961.1

Supporting:

蒋雯, 孙超, 王珏, 辛倩, 李开霖, 亓同钢, 栾云. 黄芩苷通过抑制血管重构对实验性肺动脉高压的治疗作用研究[J]. 中国药学(英文版), 2020, 29(10): 719-728.

Wen Jiang, Chao Sun, Jue Wang, Qian Xin, Kailin Li, Tonggang Qi, Yun Luan. Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(10): 719-728.

参考文献

[1] Yang, J.; Li, X.H.; Al-Lamki, R.S.; Southwood, M.; Zhao, J.; Lever, A.M.; Grimminger, F.; Schermuly, R.T.; Morrell, N.W. Smad-dependent and smad-independent induction of Id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ. Res. 2010, 107, 252-262.

[2] Lavoie, J.R.; Ormiston, M.L.; Perez-Iratxeta, C.; Courtman, D.W.; Jiang, B.H.; Ferrer, E.; Caruso, P.; Southwood, M.; Foster, W.S.; Morrell, N.W.; Stewart, D.J. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014, 129, 2125-2135.

[3] Pietra, G.G.; Capron, F.; Stewart, S.; Leone, O.; Humbert, M.; Robbins, I.M.; Reid, L.M.; Tuder, R.M. Pathologic assessment of vasculopathies in pulmonary hypertension. J. Am. Coll. Cardiol. 2004, 43, S25-S32.

[4] Pietra, G.G.; Edwards, W.D.; Kay, J.M.; Rich, S.; Kernis, J.; Schloo, B.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation. 1989, 80, 1198-1206.

[5] Zhao, C.F.; Wang, L.J.; Gao, L.; Xia, W.; Wang, Z.Y.; Li, F.H. Changes and distributions of peptides derived from proadrenomedullin in left-to-right shunt pulmonary hypertension of rats. Circ. J. 2008, 72, 476-481.

[6] Stenmark, K.R.; Fagan, K.A.; Frid, M.G. Hypoxia-induced pulmonary vascular remodeling cellular and molecular mechanisms. Circ. Res. 2006, 99, 675-691.

[7] Hosokawa, S.; Haraguchi, G.; Sasaki, A.; Arai, H.; Muto, S.; Itai, A.; Doi, S.; Mizutani, S.; Isobe, M. Pathophysiological roles of nuclear factor kappa B (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354. Cardiovasc. Res. 2013, 99, 35-43.

[8] Wang, Y.Y.; Luan, Y.; Zhang, X.; Lin, M.; Zhang, Z.H.; Zhu, X.B.; Ma, Y.; Wang, Y.B. Proteasome inhibitor PS-341 attenuates flow-induced pulmonary arterial hypertension. Clin. Exp. Med. 2014, 14, 321-329.

[9] Jin, U.H.; Suh, S.J.; Chang, H.W.; Son, J.K.; Lee, S.H.; Son, K.H.; Chang, Y.C.; Kim, C.H. Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. J. Cell. Biochem. 2008, 104, 15-26.

[10] Kumar, S.; Wei, C.; Thomas, C.M.; Kim, I.K.; Seqqat, R.; Kumar, R.; Baker, K.M.; Jones, W.K.; Gupta, S. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1655-H1666.

[11] Luan, Y.; Chao, S.; Ju, Z.Y.; Wang, J.; Xue, X.; Qi, T.G.; Cheng, G.H.; Kong, F. Therapeutic effects of baicalin on monocrotaline-induced pulmonary arterial hypertension by inhibiting inflammatory response. Int. Immunopharmacol. 2015, 26, 188-193.

[12] Shen, Y.C.; Chiou, W.F.; Chou, Y.C.; Chen, C.F. Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. Eur. J. Pharmacol. 2003, 465, 171-181.

[13] Chen, Y.; Hui, H.; Yang, H.; Zhao, K.; Qin, Y.S.; Gu, C.; Wang, X.T.; Lu, N.; Guo, Q.L. Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells. Blood. 2013, 121, 3682-3691.

[14] Woo, A.Y.H.; Cheng, C.H.K.; Waye, M.M.Y. Baicalein protects rat cardiomyocytes from hypoxia/reoxygenation damage via a prooxidant mechanism. Cardiovasc. Res. 2005, 65, 244-253.

[15] Lin, L.; Wu, X.D.; Davey, A.K.; Wang, J.P. The anti-inflammatory effect of baicalin on hypoxia/reoxygenation and TNF-α induced injury in cultural rat cardiomyocytes. Phytother. Res. 2010, 24, 429-437.

[16] Zhang, L.; Pu, Z.C.; Wang, J.S.; Zhang, Z.F.; Hu, D.M.; Wang, J.J. Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway. Int. J. Mol. Sci. 2014, 15, 8153-8168.

[17] Dong, L.H.; Wen, J.K.; Miao, S.B.; Jia, Z.H.; Hu, H.J.; Sun, R.H.; Wu, Y.L.; Han, M. Erratum: Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRβ-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia. Cell Res. 2011, 21, 1276.

[18] Ikezoe, T.; Chen, S.S.; Heber, D.; Taguchi, H.; Koeffler, H.P. Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest. Prostate. 2001, 49, 285-292.

[19] D’Alto, M.; Mahadevan, V.S. Pulmonary arterial hypertension associated with congenital heart disease. Eur. Respir. Rev. 2012, 21, 328-337.

[20] Dai, H.L.; Guo, Y.; Guang, X.F.; Xiao, Z.C.; Zhang, M.; Yin, X.L. The changes of serum angiotensin-converting enzyme 2 in patients with pulmonary arterial hypertension due to congenital heart disease. Cardiology. 2013, 124, 208-212.

[21] Li, L.; Wei, C.; Kim, I.K.; Janssen-Heininger, Y.; Gupta, S. Inhibition of nuclear factor-κB in the lungs prevents monocrotaline-induced pulmonary hypertension in mice. Hypertens. Dallas Tex. 2014, 63, 1260-1269.

[22] Zhang, X.; Wang, Z.S.; Luan, Y.; Lin, M.; Zhu, X.B.; Ma, Y.; Zhang, Z.H.; Wang, Y.B. The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension. Int. J. Mol. Med. 2014, 33, 105-110.

[23] Chen, Y.; Hui, H.; Yang, H.; Zhao, K.; Qin, Y.S.; Gu, C.; Wang, X.T.; Lu, N.; Guo, Q.L. Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells. Blood. 2013, 121, 3682-3691.

[24] Morrell, N.W.; Bloch, D.B.; Dijke, P.T.; Goumans, M.J.T.H.; Hata, A.; Smith, J.; Yu, P.B.; Bloch, K.D. Targeting BMP signalling in cardiovascular disease and anaemia. Nat. Rev. Cardiol. 2016, 13, 106.

[25] Lowery, J.W.; Frump, A.L.; Anderson, L.; DiCarlo, G.E.; Jones, M.T.; de Caestecker, M.P. ID family protein expression and regulation in hypoxic pulmonary hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 299, R1463-R1477.

[26] Ciumas, M.; Eyries, M.; Poirier, O.; Maugenre, S.; Dierick, F.; Gambaryan, N.; Montagne, K.; Nadaud, S.; Soubrier, F. Bone morphogenetic proteins protect pulmonary microvascular endothelial cells from apoptosis by upregulating α-B-crystallin. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2577-2584.

[27] Kumar, S.; Wei, C.; Thomas, C.M.; Kim, I.K.; Seqqat, R.; Kumar, R.; Baker, K.M.; Jones, W.K.; Gupta, S. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1655-H1666.

[28] Hurst, L.A.; Dunmore, B.J.; Long, L.; Crosby, A.; Al-Lamki, R.; Deighton, J.; Southwood, M.; Yang, X.D.; Nikolic, M.Z.; Herrera, B.; Inman, G.J.; Bradley, J.R.; Rana, A.A.; Upton, P.D.; Morrell, N.W. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat. Commun. 2017, 8, 14079.

[29] Murphy, N.; Gaynor,K.U.; Rowan,S.C.; Walsh, S.M.; Fabre, A.; Boylan, J.; Keane, M.P.; McLoughlin, P. Altered expression ofbone morphogenetic protein accessory proteins in murine and human pulmonary fibrosis. Am. J. Pathol. 2016, 186, 600-615.

[30] Arciniegas, E.; Frid, M.G.; Douglas, I.S.; Stenmark, K.R. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 2007, 293, L1-L8.

[31] Willis, B.C.; Borok, Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell Mol. Physiol. 2007, 293, L525-L534.

[32] Alastalo, T.P.; Li, M.L.; Perez, V.D.J.; Pham, D.; Sawada, H.; Wang, J.K.; Koskenvuo, M.; Wang, L.L.; Freeman, B.A.; Chang, H.Y.; Rabinovitch, M. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J. Clin. Investig. 2011, 121, 3735-3746.

黄芩苷通过抑制血管重构对实验性肺动脉高压的治疗作用研究

Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling

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