川芎嗪对野百合碱诱导大鼠肺动脉高压的影响及机制

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Effects and mechanism of tetramethylpyrazine on monocrotaline induced pulmonary arterial hypertension in rats

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doi:10.6040/j.issn.1671-7554.0.2022.0107

Abstract: Objective To investigate the effects and mechanism of tetramethylpyrazine(TMP)on monocrotaline(MCT)induced pulmonary arterial hypertension(PAH)in rats. Methods A total of 36 male SD rats were randomly divided into control, model and TMP groups, with 12 rats in each group. The rats in the model and TMP groups were given intraperitoneal injection of MCT 50 mg/kg on the 1st day to establish PAH model. After 28 days, the TMP group was given tetramethylpyrazine 80 mg/kg by gavage once a day for 4 weeks. At the end of the experiment, the right ventricular systolic pressure(RVSP)was detected and right ventricular hypertrophy index(RVHI)was counted; the pathomorphological changes of lung tissue were observed with hematoxylin-eosin(HE)staining and Masson staining, and the percentage of wall thickness(WT%)and wall area(WA%)were calculated. The structure of lung tissue was observed with a transmission electron microscope. The expressions of Hippo signal pathway related proteins YAP1, WWTR1 and TEAD1 in lung tissue were detected with immunohistochemical staining and Western blotting. Results Compared with the control group, the model group had increased RVSP and RVHI(P<0.001, P<0.001), significantly narrowed lumen of pulmonary arteries, proliferated collagen fibers, and increased protein expressions of YAP1, WWTR1 and TEAD1(P=0.004, P<0.001, P=0.013). Compared with the model group, the TMP group had decreased RVSP and RVHI(P=0.001, P<0.001), improved pulmonary artery remodeling and right ventricular hypertrophy, reduced fibrosis, and decreased protein expressions of YAP1, WWTR1 and TEAD1(P=0.045, P=0.011, P=0.034). Compared with the control group, the TMP group had increased RVSP and RVHI(P=0.045, P=0.045), and increased protein expressions of YAP1, WWTR1 and TEAD1(P=0.080, P=0.013, P=0.468), in which, the difference of WWTR1 protein expression was significant, suggesting that TMP has limited effects. Conclusion TMP has effects on MCT-induced PAH rat model. The underlying mechanism may be related to the inhibition of expressions of Hippo signal pathway related proteins.

Key words: Tetramethylpyrazine, Pulmonary arterial hypertension, Hippo signaling pathway, Pulmonary vascular remodeling, Yes-associated protein 1

CLC Number:

R544

ZENG Yuanyuan, YANG Dongpeng, DONG Zhu, ZHANG Ben, CAO Yiqiu, WANG Xiaowu. Effects and mechanism of tetramethylpyrazine on monocrotaline induced pulmonary arterial hypertension in rats[J].Journal of Shandong University (Health Sciences), 2022, 60(11): 63-69.

[1]	中华医学会呼吸病学分会肺栓塞与肺血管病学组, 中国医师协会呼吸医师分会肺栓塞与肺血管病工作委员会, 全国肺栓塞与肺血管病防治协作组, 等. 中国肺动脉高压诊断与治疗指南(2021版)[J]. 中华医学杂志, 2021, 101(1): 11-51.
[2]	Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension [J]. Lancet Respir Med, 2016, 4(4): 306-322.
[3]	Sun W, Chan SY. Pulmonary arterial stiffness: an early and pervasive driver of pulmonary arterial hypertension [J]. Front Med(Lausanne), 2018, 204(5): 1-8.
[4]	Deshwal H, Weinstein T, Sulica R. Advances in the management of pulmonary arterial hypertension [J]. Investig Med, 2021, 69(7): 1270-1280.
[5]	Kudryashova TV, Goncharov DA, Pena A, et al. Hippo-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension [J]. Am J Respir Crit Care Med, 2016, 194(7): 866-877.
[6]	Wang Q, Shi W, Zhang Q, et al. Inhibition of Siah2 ubiquitin ligase ameliorates monocrotaline-induced pulmonary arterial remodeling through inactivation of YAP [J]. Life Sci, 2020, 242: 117159. doi: 10.1016/j.lfs.2019.117159.
[7]	Xiang L, Li Y, Deng X, et al. Natural plant products in treatment of pulmonary arterial hypertension [J]. Pulm Circ, 2018, 8(3): 1-44.
[8]	Jin H, Lian N, Zhang F, et al. Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine [J]. Eur J Pharm Sci, 2017, 96: 323-333. doi: 10.1016/j.ejps.2016.10.002.
[9]	杨永超, 杨东鹏, 杨博, 等. 野百合碱诱导的肺动脉高压大鼠心肺组织变化研究[J]. 中国呼吸与危重监护杂志, 2015, 14(4): 380-384. YANG Yongchao, YANG Dongpeng, YANG Bo, et al. Pathological changes of heart and lung tissues in rats with pulmonary hypertension induced by monocrotaline [J]. Chinese Journal of Respiratory and Critical Care Medicine, 2015, 14(4): 380-384.
[10]	刘莹, 董文鹏, 陈长富, 等. Caspase-1抑制剂在野百合碱诱导的肺动脉高压大鼠中的作用[J]. 广东医学, 2017, 38(23): 3566-3570. LIU Ying, DONG Wenpeng, CHEN Changfu, et al. Effect of caspase-1 inhibitor on rats with pulmonary hypertension induced by monocrotaline [J]. Guangdong Medical Journal, 2017, 38(23): 3566-3570.
[11]	刘莹, 董文鹏, 陈长富, 等. 粉防己碱对肺动脉高压大鼠中NLRP3炎性小体表达研究[J]. 临床心血管病杂志, 2017, 33(11): 1102-1106. LIU Ying, DONG Wenpeng, CHEN Changfu, et al. Impact of the NLRP3 inflammasome on tetrandrine in rats with pulmonary arterial hypertension [J]. Journal of Clinical Cardiology(China), 2017, 33(11): 1102-1106.
[12]	Huang H, Kong L, Luan S, et al. Ligustrazine suppresses platelet-derived growth factor-BB-induced pulmonary artery smooth muscle cell proliferation and inflammation by regulating the PI3K/AKT signaling pathway [J]. Am J Chin Med, 2021, 49(2): 437-459.
[13]	Chen Y, Lu W, Yang K, et al. Tetramethylpyrazine: a promising drug for the treatment of pulmonary hypertension [J]. Br J Pharmacol, 2020, 177(12): 2743-2764.
[14]	杨东鹏, 杨永超, 吕珊珊, 等. iNOS和PKG-1在白藜芦醇防治肺动脉高压中的作用[J]. 实用医学杂志, 2015, 31(10): 1577-1579. YANG Dongpeng, YANG Yongchao, LYU Shanshan, et al. Mechanism of resveratrol in prevention and treatment of pulmonary artery hypertension [J]. The Journal of Practical Medicine, 2015, 31(10): 1577-1579.
[15]	Ge XY, Zhu TT, Yao MZ, et al. MicroRNA-137 inhibited hypoxia-induced proliferation of pulmonary artery smooth muscle cells by targeting calpain-2 [J]. Biomed Res Int, 2021, 2021: 2202888. doi: 10.1155/2021/2202888.
[16]	吉新彦, 钟国轩, 赵斌. 哺乳动物Hippo信号通路分子机制研究进展[J]. 遗传, 2017, 39(7): 546-567. JI Xinyan, ZHONG Guoxuan, ZHAO Bin. Molecular mechanisms of the mammalian hippo signaling pathway [J]. Hereditas(Beijing), 2017, 39(7): 546-567.
[17]	Yu Y, Su X, Qin Q, et al. Yes-associated protein and transcriptional coactivator with PDZ-binding motif as new targets in cardiovascular diseases [J]. Pharmacol Res, 2020, 159: 105009. doi: 10.1016/j.phrs.2020.105009.
[18]	Acharya AP, Tang Y, Bertero T, et al. Simultaneous pharmacologic inhibition of yes-associated protein 1 and glutaminase 1 via inhaled poly(lactic-co-glycolic)acid-encapsulated microparticles improves pulmonary hypertension [J]. J Am Heart Assoc, 2021, 10(12): 1-15.
[19]	Zuo W, Liu N, Zeng Y, et al. Luteolin ameliorates experimental pulmonary arterial hypertension via suppressing hippo-YAP/PI3K/AKT signaling pathway [J]. Front Pharmacol, 2021, 12: doi: 10.3389/fphar.2021.663551.
[20]	Zhang Q, Li W, Zhu Y, et al. Activation of AMPK inhibits galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP [J]. Mol Cell Biochem, 2021, 476(8): 3037-3049.
[21]	Mandras SA, Mehta HS, Vaidya A. Pulmonary hypertension: a brief guide for clinicians [J]. Mayo Clin Proc, 2020, 95(9): 1978-1988.
[22]	Gaine S, Mclaughlin V. Pulmonary arterial hypertension: tailoring treatment to risk in the current era [J]. Eur Respir Rev, 2017, 26(146): 1-10.
[23]	Yu L, Huang X, Huang K, et al. Ligustrazine attenuates the platelet-derived growth factor-BB-induced proliferation and migration of vascular smooth muscle cells by interrupting extracellular signal-regulated kinase and P38 mitogen-activated protein kinase pathways [J]. Mol Med Rep, 2015, 12(1): 705-711.
[24]	Peng C, Zhang S, Liu H, et al. A newly synthesized ligustrazine stilbene derivative inhibits PDGF-BB induced vascular smooth muscle cell phenotypic switch and proliferation via delaying cell cycle progression [J]. Eur J Pharmacol, 2017, 814: 106-113. doi: 10.1016/j.ejphar.2017.08.008.
[25]	杨敏, 李慧, 朱博文, 等. 川芎嗪抑制血管重塑的研究进展[J]. 中国中西医结合杂志, 2018, 38(3): 379-383.

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