Shexiang Tongxin dropping pills ameliorate myocardial ischemia-reperfusion injury progression via the S1PR2/RhoA/ROCK pathway
), Chun Lib,e,f()Abstract
To investigate the potential protective effect of Shexiang Tongxin dropping pills (STDP) on ischemia-reperfusion injury and its underlying mechanisms in improving endothelial cell function in coronary microvascular disease (CMVD).
A rat model of myocardial ischemia-reperfusion injury with CMVD was established using ligation and reperfusion of the left anterior descending artery. The effect of STDP (21.6 mg/kg) on cardiac function was evaluated using echocardiography, hematoxylin-eosin staining, and Evans blue staining. The effects of STDP on the microvascular endothelial barrier were assessed based on nitric oxide production, endothelial nitric oxide synthase expression, structural variety of tight junctions (TJs), and the expression of zonula occludens-1 (ZO-1), claudin-5, occludin, and vascular endothelial (VE)-cadherin proteins. The mechanisms of STDP (50 and 100 ng/mL) were evaluated by examining the expression of sphingosine 1-phosphate receptor 2 (S1PR2), Ras Homolog family member A (RhoA), and Rho-associated coiled-coil-containing protein kinase (ROCK) proteins and the distribution of ZO-1, VE-cadherin, and F-actin proteins in an oxygen and glucose deprivation/reoxygenation model.
The administration of STDP on CMVD rat model significantly improved cardiac and microvascular endothelial cell barrier functions (all P <.05). STDP enhanced the structural integrity of coronary microvascular positioning and distribution by clarifying and completing TJs and increasing the expression of ZO-1, occludin, claudin-5, and VE-cadherin in vivo (all P <.05). The S1PR2/RhoA/ROCK pathway was inhibited by STDP in vitro, leading to the regulation of endothelial cell TJs, adhesion junctions, and cytoskeletal morphology.
STDP showed protective effects on cardiac impairment and microvascular endothelial barrier injury in CMVD model rats induced by myocardial ischemia-reperfusion injury through the modulation of the S1PR2/RhoA/ROCK pathway.
Keywords
References
Chen W, Ni M, Huang H, et al. Chinese expert consensus on the diagnosis and treatment of coronary microvascular diseases (2023 Edition). MedComm (2020). 2023;4(6):e438.
Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35(17):1101-1111.
Thakker RA, Rodriguez Lozano J, Rodriguez Lozano P, et al. Coronary microvascular disease. Cardiol Ther. 2022;11(1):23-31.
Kunadian V, Chieffo A, Camici PG, et al. An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on coronary pathophysiology & microcirculation endorsed by Coronary Vasomotor Disorders International Study Group. Eur Heart J. 2020;41(37):3504-3520.
Fukushima K, Javadi MS, Higuchi T, et al. Prediction of short-term cardiovascular events using quantification of global myocardial flow reserve in patients referred for clinical 82Rb PET perfusion imaging. J Nucl Med. 2011;52(5):726-732.
Marinescu MA, Löffler AI, Ouellette M, Smith L, Kramer CM, Bourque JM. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging. 2015;8(2):210-220.
Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation. 2011;124(20):2215-2224.
Ahmadi A, Dabidi Roshan V, Jalali A. Coronary vasomotion and exercise-induced adaptations in coronary artery disease patients: a systematic review and meta-analysis. J Res Med Sci. 2020;25:76.
Witkowski M, Witkowski M, Friebel J, et al. Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis. Cardiovasc Res. 2022;118(10):2367-2384.
Yang Z, Lin S, Liu Y, et al. Traditional Chinese medicine in coronary microvascular disease. Front Pharmacol. 2022;13:929159.
Wettschureck N, Strilic B, Offermanns S. Passing the vascular barrier: endothelial signaling processes controlling extravasation. Physiol Rev. 2019;99(3):1467-1525.
Weis SM. Vascular permeability in cardiovascular disease and cancer. Curr Opin Hematol. 2008;15(3):243-249.
Cartier A, Hla T. Sphingosine 1-phosphate: lipid signaling in pathology and therapy. Science. 2019;366(6463):eaar5551.
Tsai HC, Han MH. Sphingosine-1-phosphate (S1P) and S1P signaling pathway: therapeutic targets in autoimmunity and inflammation. Drugs. 2016;76(11):1067-1079.
Warboys CM, Weinberg PD. S1P in the development of atherosclerosis: roles of hemodynamic wall shear stress and endothelial permeability. Tissue Barriers. 2021;9(4):1959243.
Li Q, Chen B, Zeng C, et al. Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. Exp Physiol. 2015;100(1):95-107.
Lu X, Yao J, Li C, et al. Shexiang Tongxin dropping pills promote macrophage polarization-induced angiogenesis against coronary microvascular dysfunction via PI3K/Akt/mTORC1 pathway. Front Pharmacol. 2022;13:840521.
Cui L, Liu Y, Hu Y, et al. Shexiang Tongxin dropping pill alleviates M1 macrophage polarization-induced inflammation and endothelial dysfunction to reduce coronary microvascular dysfunction via the Dectin-1/Syk/IRF5 pathway. J Ethnopharmacol. 2023;316:116742.
Cui XY, Liu TH, Bai YL, et al. Shexiang Tongxin dropping pill promotes angiogenesis through VEGF/eNOS signaling pathway on diabetic coronary microcirculation dysfunction. Chin J Integr Med. 2024;30(10):886-895.
Liu H, Zhao J, Pan S, et al. Shexiang Tongxin dropping pill protects against sodium laurate-induced coronary microcirculatory dysfunction in rats. J Tradit Chin Med. 2021;41(1):89-97.
Wang Y, Wang T, Ma T, Zhao J, Qi W. Shexiang tongxin dropping pill alleviates myocardial injury induced by coronary microembolization by down-regulating APOC1 to inhibit STAT3 signaling pathway. Aging (Albany NY). 2024;16(10):8484-8496.
Lu W, Wang Q, Sun X, et al. Qishen granule improved cardiac remodeling via balancing M1 and M2 macrophages. Front Pharmacol. 2019;10:1399.
Lin M, Xu CL, Pan HY, et al. Quality evaluation of Shexiang Tongxin dropping pill based on HPLC fingerprints combined with HPLC-Q-TOF-MS/MS method. J Chromatogr Sci. 2024;62(8):732-741.
Zhang Q, Shi J, Guo D, et al. Qishen granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia. J Ethnopharmacol. 2020;252:112573.
Tian X, Chen X, Jiang Q, et al. Notoginsenoside R1 ameliorates cardiac lipotoxicity through AMPK signaling pathway. Front Pharmacol. 2022;13:864326.
He Z, Du J, Zhang Y, et al. Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux. Theranostics. 2023;13(2):849-866.
Zhang S, Liu H, Fang Q, et al. Shexiang Tongxin dropping pill protects against chronic heart failure in mice via inhibiting the ERK/MAPK and TGF-β signaling pathways. Front Pharmacol. 2021;12:796354.
Project Team of Guidelines for Integrated Chinese and Western Medicine in the Diagnosis and Treatment of Coronary Artery Microangiopathy. Guidelines for integrated Chinese and Western medicine in the diagnosis and treatment of coronary artery microangiopathy. Chin J Integr Tradit West Med. 2023;43(9):1029-1039 [Chinese].
Yang Z, Liu Y, Song Z, et al. Chinese patent medicines for coronary microvascular disease: clinical evidence and potential mechanisms. Int J Med Sci. 2023;20(8):1024-1037.
Zhong S, Li J, Chen J, et al. Exploring the pathogenesis and treatment of vascular endothelial injury in coronary heart disease based on the toxic pathogen theory. J Beijing Univ Tradit Chin Med. 2023;46(7):985-991 [Chinese].
Heusch G, Deussen A, Thämer V. Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst. 1985;13(4):311-326.
Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1):92-100.
Gao XM, Wu QZ, Kiriazis H, et al. Microvascular leakage in acute myocardial infarction: characterization by histology, biochemistry, and magnetic resonance imaging. Am J Physiol Heart Circ Physiol. 2017;312(5):H1068-H1075.
Xiong M, Jia C, Cui J, et al. Shexiang Tongxin dropping pill attenuates atherosclerotic lesions in ApoE deficient mouse model. J Ethnopharmacol. 2015;159:84-92.
Lin YJ, Jiao KL, Liu B, Fang L, Meng S. Antiplatelet and myocardial protective effect of Shexiang Tongxin dropping pill in patients undergoing percutaneous coronary intervention: a randomized controlled trial. J Integr Med. 2022;20(2):126-134.
Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C. Treatment of coronary microvascular dysfunction. Cardiovasc Res. 2020;116(4):856-870.
Wu Y, Lin Y, Liu B, et al. Shexiang Tongxin dropping pill ameliorates microvascular obstruction via downregulating ALOX12 after myocardial ischemia-reperfusion. Int J Cardiol. 2024;416:132481.
Ding Y, Zhu HY, Zhang LZ, Gao BB, Zhou L, Huang JY. Shexiang Tongxin dropping pill reduces coronary microembolization in rats via regulation of mitochondrial permeability transition pore opening and AKT-GSK3β phosphorylation. Chin J Integr Med. 2021;27(7):527-533.
Zhou C, Kuang Y, Li Q, et al. Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway. Theranostics. 2022;12(11):5172-5188.
Wang X, Chen S, Xiang H, et al. S1PR2/RhoA/ROCK1 pathway promotes inflammatory bowel disease by inducing intestinal vascular endothelial barrier damage and M1 macrophage polarization. Biochem Pharmacol. 2022;201:115077.
Bloom SI, Islam MT, Lesniewski LA, Donato AJ. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol. 2023;20(1):38-51.
Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers. 2015;1:15015.
Shimokawa H, Satoh K. Light and dark of reactive oxygen species for vascular function: 2014 ASVB (Asian Society of Vascular Biology). J Cardiovasc Pharmacol. 2015;65(5):412-418.
Yang J, Ruan F, Zheng Z. Ripasudil attenuates lipopolysaccharide (LPS)-mediated apoptosis and inflammation in pulmonary microvascular endothelial cells via ROCK2/eNOS signaling. Med Sci Mon Int Med J Exp Clin Res. 2018;24:3212-3219.
Wang SH, Chu L, Xu Z, Zhou HL, Chen JF, Ning HF. Effect of Shexiang Tongxin dropping pills on the immediate blood flow of patients with coronary slow flow. Chin J Integr Med. 2019;25(5):360-365.
Zhang Y, Zhao J, He Z, Shi S, Liang C, Wu Z. Shexiang Tongxin dropping pill improves peripheral microvascular blood flow via cystathionine-γ-lyase. Med Sci Mon Int Med J Exp Clin Res. 2019;25:6313-6321.
Lu Y, Chu X, Zhang J, et al. Effect of Shexiang Tongxin dropping pill on stable coronary artery disease patients with normal fractional flow reserve and coronary microvascular disease: a study protocol. Medicine (Baltim). 2020;99(38):e22126.
Kim JG, Islam R, Cho JY, et al. Regulation of RhoA GTPase and various transcription factors in the RhoA pathway. J Cell Physiol. 2018;233(9):6381-6392.
Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-Kinase in the cardiovascular system. Circ Res. 2016;118(2):352-366.
Chen J, Sun L, Ding GB, et al. Oxygen-glucose deprivation/reoxygenation induces human brain microvascular endothelial cell hyperpermeability via VE-cadherin internalization: roles of RhoA/ROCK2. J Mol Neurosci. 2019;69(1):49-59.
Pan CS, Yan L, Lin SQ, et al. QiShenYiQi pills attenuates ischemia/reperfusion-induced cardiac microvascular hyperpermeability implicating Src/caveolin-1 and RhoA/ROCK/MLC signaling. Front Physiol. 2021;12:753761.
Lee JF, Zeng Q, Ozaki H, et al. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J Biol Chem. 2006;281(39):29190-29200.
Xu M, Waters CL, Hu C, Wysolmerski RB, Vincent PA, Minnear FL. Sphingosine 1-phosphate rapidly increases endothelial barrier function independently of VE-cadherin but requires cell spreading and Rho kinase. Am J Physiol Cell Physiol. 2007;293(4):C1309-C1318.
Luo SY, Chen S, Qin YD, Chen ZW. Urotensin-Ⅱ receptor antagonist SB-710411 protects rat heart against ischemia-reperfusion injury via RhoA/ROCK pathway. PLoS One. 2016;11(1):e0146094.
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