Magnesium Lithospermate B Derived from Salvia miltiorrhiza Ameliorates Right Ventricle Remodeling in Pulmonary Hypertensive Rats via Inhibition of NOX/VPO1 Pathway

Tao Li; Jing-Jie Peng; E-Li Wang; Nian-Sheng Li; Feng-Lin Song; Jin-Fu Yang; Xiu-Ju Luo; Bin Liu; Jun Peng

doi:10.1055/a-0863-4741

Planta Medica, Table of Contents

Planta Med 2019; 85(09/10): 708-718
DOI: 10.1055/a-0863-4741

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Magnesium Lithospermate B Derived from Salvia miltiorrhiza Ameliorates Right Ventricle Remodeling in Pulmonary Hypertensive Rats via Inhibition of NOX/VPO1 Pathway

Tao Li

¹Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

,

Jing-Jie Peng

²Department of Laboratory Medicine, the third Xiangya Hospital of Central South University, Changsha, China

,

E-Li Wang

¹Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

,

Nian-Sheng Li

¹Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

,

Feng-Lin Song

³Department of cardiovascular surgery, the second Xiangya Hospital, Central South University, Changsha, China

,

Jin-Fu Yang

³Department of cardiovascular surgery, the second Xiangya Hospital, Central South University, Changsha, China

,

Xiu-Ju Luo

²Department of Laboratory Medicine, the third Xiangya Hospital of Central South University, Changsha, China

,

Bin Liu

¹Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

⁴Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China

,

Jun Peng

¹Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

⁵Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China

› Author Affiliations

Abstract

Right ventricle (RV) remodeling is a major pathological feature in pulmonary arterial hypertension (PAH). Magnesium lithospermate B (MLB) is a compound isolated from the roots of Salvia miltiorrhiza and it possesses multiple pharmacological activities such as anti-inflammation and antioxidation. This study aims to investigate whether MLB is able to prevent RV remodeling in PAH and the underlying mechanisms. In vivo, SD rats were exposed to 10% O₂ for 21 d to induce RV remodeling, which showed hypertrophic features (increases in the ratio of RV weight to tibia length, cellular size, and hypertrophic marker expression), accompanied by upregulation in expression of NADPH oxidases (NOX2 and NOX4) and vascular peroxidase 1 (VPO1), increases in hydrogen peroxide (H₂O₂) and hypochlorous acid (HOCl) production and elevation in phosphorylation levels of ERK; these changes were attenuated by treating rats with MLB. In vitro, the cultured H9c2 cells were exposed to 3% O₂ for 24 h to induce hypertrophy, which showed hypertrophic features (increases in cellular size and hypertrophic marker expression). Administration of MLB or VAS2870 (a positive control for NOX inhibitor) could prevent cardiomyocyte hypertrophy concomitant with decreases in NOX (NOX2 and NOX4) and VPO1 expression, H₂O₂ and HOCl production, and ERK phosphorylation. Based on these observations, we conclude that MLB is able to prevent RV remodeling in hypoxic PAH rats through a mechanism involving a suppression of NOX/VPO1 pathway as well as ERK signaling pathway. MLB may possess the potential clinical value for PAH therapy.

Key words

Salvia miltiorrhiza - Lamiaceae - pulmonary arterial hypertension - magnesium lithospermate B - right ventricle remodeling - NADPH oxidase - vascular peroxidase1

Full Text

References

References
1 van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg MD, Postmus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007; 28: 1250-1257
2 Mehta D, Lubitz SA, Frankel Z, Wisnivesky JP, Einstein AJ, Goldman M, Machac J, Teirstein A. Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing. Chest 2008; 133: 1426-1435
3 Nagata Y, Konno T, Fujino N, Hodatsu A, Nomura A, Hayashi K, Nakamura H, Kawashiri MA, Yamagishi M. Right ventricular hypertrophy is associated with cardiovascular events in hypertrophic cardiomyopathy: evidence from study with magnetic resonance imaging. Can J Cardiol 2015; 31: 702-708
4 Kojonazarov B, Luitel H, Sydykov A, Dahal BK, Paul-Clark MJ, Bonvini S, Reed A, Schermuly RT, Mitchell JA. The peroxisome proliferator-activated receptor beta/delta agonist GW0742 has direct protective effects on right heart hypertrophy. Pulm Circ 2013; 3: 926-935
5 Moreira-Goncalves D, Ferreira R, Fonseca H, Padrao AI, Moreno N, Silva AF, Vasques-Novoa F, Goncalves N, Vieira S, Santos M, Amado F, Duarte JA, Leite-Moreira AF, Henriques-Coelho T. Cardioprotective effects of early and late aerobic exercise training in experimental pulmonary arterial hypertension. Basic Res Cardiol 2015; 110: 57
6 Liu B, Luo XJ, Yang ZB, Zhang JJ, Li TB, Zhang XJ, Ma QL, Zhang GG, Hu CP, Peng J. Inhibition of NOX/VPO1 pathway and inflammatory reaction by trimethoxystilbene in prevention of cardiovascular remodeling in hypoxia-induced pulmonary hypertensive rats. J Cardiovasc Pharmacol 2014; 63: 567-576
7 Li Y, Li Y, Shi F, Wang L, Li L, Yang D. Osthole attenuates right ventricular remodeling via decreased myocardial apoptosis and inflammation in monocrotaline-induced rats. Eur J Pharmacol 2018; 818: 525-533
8 Zhang YS, Liu B, Luo XJ, Li TB, Zhang JJ, Peng JJ, Zhang XJ, Ma QL, Hu CP, Li YJ, Peng J, Li Q. Nuclear cardiac myosin light chain 2 modulates NADPH oxidase 2 expression in myocardium: a novel function beyond muscle contraction. Basic Res Cardiol 2015; 110: 38
9 Lou Z, Ren KD, Tan B, Peng JJ, Ren X, Yang ZB, Liu B, Yang J, Ma QL, Luo XJ, Peng J. Salviaolate protects rat brain from ischemia-reperfusion injury through inhibition of NADPH oxidase. Planta Med 2015; 81: 1361-1369
10 Matsushima S, Tsutsui H, Sadoshima J. Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med 2014; 24: 202-205
11 Liao Y, Gou L, Chen L, Zhong X, Zhang D, Zhu H, Lu X, Zeng T, Deng X, Li Y. NADPH oxidase 4 and endothelial nitric oxide synthase contribute to endothelial dysfunction mediated by histone methylations in metabolic memory. Free Radic Biol Med 2018; 115: 383-394
12 Liu B, Li T, Peng JJ, Zhang JJ, Liu WQ, Luo XJ, Ma QL, Gong ZC, Peng J. Non-muscle myosin light chain promotes endothelial progenitor cells senescence and dysfunction in pulmonary hypertensive rats through up-regulation of NADPH oxidase. Eur J Pharmacol 2016; 775: 67-77
13 Barman SA, Chen F, Su Y, Dimitropoulou C, Wang Y, Catravas JD, Han W, Orfi L, Szantai-Kis C, Keri G, Szabadkai I, Barabutis N, Rafikova O, Rafikov R, Black SM, Jonigk D, Giannis A, Asmis R, Stepp DW, Ramesh G, Fulton DJ. NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol 2014; 34: 1704-1715
14 Garcia-Redondo AB, Aguado A, Briones AM, Salaices M. NADPH oxidases and vascular remodeling in cardiovascular diseases. Pharmacol Res 2016; 114: 110-120
15 Frazziano G, Al Ghouleh I, Baust J, Shiva S, Champion HC, Pagano PJ. Nox-derived ROS are acutely activated in pressure overload pulmonary hypertension: indications for a seminal role for mitochondrial Nox4. Am J Physiol Heart Circ Physiol 2014; 306: H197-H205
16 Chen F, Li X, Aquadro E, Haigh S, Zhou J, Stepp DW, Weintraub NL, Barman SA, Fulton DJR. Inhibition of histone deacetylase reduces transcription of NADPH oxidases and ROS production and ameliorates pulmonary arterial hypertension. Free Radic Biol Med 2016; 99: 167-178
17 Peng JJ, Liu B, Xu JY, Peng J, Luo XJ. NADPH oxidase: its potential role in promotion of pulmonary arterial hypertension. Naunyn Schmiedebergs Arch Pharmacol 2017; 390: 331-338
18 Zhang YS, He L, Liu B, Li NS, Luo XJ, Hu CP, Ma QL, Zhang GG, Li YJ, Peng J. A novel pathway of NADPH oxidase/vascular peroxidase 1 in mediating oxidative injury following ischemia-reperfusion. Basic Res Cardiol 2012; 107: 266
19 Park CH, Shin SH, Lee EK, Kim DH, Kim MJ, Roh SS, Yokozawa T, Chung HY. Magnesium lithospermate B from Salvia miltiorrhiza Bunge ameliorates aging-induced renal inflammation and senescence via NADPH oxidase-mediated reactive oxygen generation. Phytother Res 2017; 31: 721-728
20 Yang ZB, Luo XJ, Ren KD, Peng JJ, Tan B, Liu B, Lou Z, Xiong XM, Zhang XJ, Ren X, Peng J. Beneficial effect of magnesium lithospermate B on cerebral ischemia-reperfusion injury in rats involves the regulation of miR-107/glutamate transporter 1 pathway. Eur J Pharmacol 2015; 766: 91-98
21 Quan W, Wu B, Bai Y, Zhang X, Yin J, Xi M, Guan Y, Shao Q, Chen Y, Wu Q, Wen A. Magnesium lithospermate B improves myocardial function and prevents simulated ischemia/reperfusion injury-induced H9c2 cardiomyocytes apoptosis through Akt-dependent pathway. J Ethnopharmacol 2014; 151: 714-721
22 Du CS, Yang RF, Song SW, Wang YP, Kang JH, Zhang R, Su DF, Xie X. Magnesium lithospermate B protects cardiomyocytes from ischemic injury via inhibition of TAB1-p 38 apoptosis signaling. Front Pharmacol 2010; 1: 111
23 Choudhary G, Troncales F, Martin D, Harrington EO, Klinger JR. Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension. J Heart Lung Transplant 2011; 30: 827-833
24 Campos-Carraro C, Turck P, de Lima-Seolin BG, Tavares AMV, Dos Santos Lacerda D, Corssac GB, Teixeira RB, Hickmann A, Llesuy S, da Rosa Araujo AS, Bello-Klein A. Copaiba oil attenuates right ventricular remodeling by decreasing myocardial apoptotic signaling in monocrotaline-induced rats. J Cardiovasc Pharmacol 2018; 72: 214-221
25 Taran IN, Belevskaya AA, Saidova MA, Martynyuk TV, Chazova IE. Initial riociguat monotherapy and transition from sildenafil to riociguat in patients with idiopathic pulmonary arterial hypertension: influence on right heart remodeling and right ventricular-pulmonary arterial coupling. Lung 2018; 196: 745-753
26 Rawat DK, Alzoubi A, Gupte R, Chettimada S, Watanabe M, Kahn AG, Okada T, McMurtry IF, Gupte SA. Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure. Hypertension 2014; 64: 1266-1274
27 Konior A, Schramm A, Czesnikiewicz-Guzik M, Guzik TJ. NADPH oxidases in vascular pathology. Antioxid Redox Signal 2014; 20: 2794-2814
28 Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A, Ge J. Megakaryocytic leukemia 1 bridges epigenetic activation of NADPH oxidase in macrophages to cardiac ischemia-reperfusion injury. Circulation 2018; 138: 2820-2836
29 Adesina SE, Kang BY, Bijli KM, Ma J, Cheng J, Murphy TC, Michael Hart C, Sutliff RL. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med 2015; 87: 36-47
30 Choi SH, Gonen A, Diehl CJ, Kim J, Almazan F, Witztum JL, Miller YI. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL. Autophagy 2015; 11: 785-795
31 Manea SA, Antonescu ML, Fenyo IM, Raicu M, Simionescu M, Manea A. Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes. Redox Biol 2018; 16: 332-343
32 Wang Y, Dong J, Liu P, Lau CW, Gao Z, Zhou D, Tang J, Ng CF, Huang Y. Ginsenoside Rb3 attenuates oxidative stress and preserves endothelial function in renal arteries from hypertensive rats. Br J Pharmacol 2014; 171: 3171-3181
33 Zhang YZ, Wang L, Zhang JJ, Xiong XM, Zhang D, Tang XM, Luo XJ, Ma QL, Peng J. Vascular peroxide 1 promotes ox-LDL-induced programmed necrosis in endothelial cells through a mechanism involving beta-catenin signaling. Atherosclerosis 2018; 274: 128-138
34 You B, Liu Y, Chen J, Huang X, Peng H, Liu Z, Tang Y, Zhang K, Xu Q, Li X, Cheng G, Shi R, Zhang G. Vascular peroxidase 1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation, apoptosis resistance and migration. Cardiovasc Res 2018; 114: 188-199
35 Liu SY, Yuan Q, Li XH, Hu CP, Hu R, Zhang GG, Li D, Li YJ. Role of vascular peroxidase 1 in senescence of endothelial cells in diabetes rats. Int J Cardiol 2015; 197: 182-191
36 Altenhofer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal 2015; 23: 406-427
37 Zhang Y, Akao T, Nakamura N, Duan CL, Hattori M, Yang XW, Liu JX. Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat. Planta Med 2004; 70: 138-142
38 Tang Y, Xu Q, Peng H, Liu Z, Yang T, Yu Z, Cheng G, Li X, Zhang G, Shi R. The role of vascular peroxidase 1 in ox-LDL-induced vascular smooth muscle cell calcification. Atherosclerosis 2015; 243: 357-363