Abstract
Ischemic heart diseases (IHDs) cause great morbidity and mortality worldwide, necessitating effective treatment. Salvianic acid A sodium (SAAS) is an active compound derived from the well-known herbal medicine Danshen, which has been widely used for clinical treatment of cardiovascular diseases in China. This study aimed to confirm the cardioprotective effects of SAAS in rats with myocardial infarction and to investigate the underlying molecular mechanisms based on proteome and transcriptome profiling of myocardial tissue. The results showed that SAAS effectively protected against myocardial injury and improved cardiac function. The differentially expressed proteins and genes included important structural molecules, receptors, transcription factors, and cofactors. Functional enrichment analysis indicated that SAAS participated in the regulation of actin cytoskeleton, phagosome, focal adhesion, tight junction, apoptosis, MAPK signaling, and Wnt signaling pathways, which are closely related to cardiovascular diseases. SAAS may exert its cardioprotective effect by targeting multiple pathways at both the proteome and transcriptome levels. This study has provided not only new insights into the pathogenesis of myocardial infarction but also a road map of the cardioprotective molecular mechanisms of SAAS, which may provide pharmacological evidence to aid in its clinical application.
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References
Akhtar S. Ischemic heart disease. Anesth Clin. 2006;24:461–85.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315–81.
Xiong X, Borrelli F, de Sa Ferreira A, Ashfaq T, Feng B. Herbal medicines for cardiovascular diseases. Evid Based Complement Altern Med. 2014;2014:809741.
Cheng TO. Cardiovascular effects of Danshen. Int J Cardiol. 2007;121:9–22.
Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 2005;45:1345–59.
Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen R, et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell. 2012;148:1293–307.
Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science. 2011;333:53–8.
Wu JQ, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S, et al. Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. Proc Natl Acad Sci USA. 2010;107:5254–9.
Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456:470–6.
Muers M. Gene expression: transcriptome to proteome and back to genome. Nat Rev Genet. 2011;12:518.
Savitski MM, Wilhelm M, Hahne H, Kuster B, Bantscheff M. A scalable approach for protein false discovery rate estimation in large proteomic data sets. Mol Cell Proteomics. 2015;14:2394–404.
Tarun AS, Peng X, Dumpit RF, Ogata Y, Silva-Rivera H, Camargo N, et al. A combined transcriptome and proteome survey of malaria parasite liver stages. Proc Natl Acad Sci USA. 2008;105:305–10.
Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH, et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci USA. 2005;102:7653–8.
Wang H, Cao C, Hui L, Liu T, Wang Y, Gao S, et al. A Study of myocardial ischemia model induced by left coronary artery ligation in rats. World J Cardiovasc Dis. 2016;6:133–42.
Song Q, Chu X, Zhang X, Bao Y, Zhang Y, Guo H, et al. Mechanisms underlying the cardioprotective effect of Salvianic acid A against isoproterenol-induced myocardial ischemia injury in rats: possible involvement of L-type calcium channels and myocardial contractility. J Ethnopharmacol. 2016;189:157–64.
Meng Y, Li WZ, Shi YW, Zhou BF, Ma R, Li WP. Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-kappaB-TRPC6 pathway. Int J Mol Med. 2016;37:258–66.
Fan G, Yu J, Asare PF, Wang L, Zhang H, Zhang B, et al. Danshensu alleviates cardiac ischaemia/reperfusion injury by inhibiting autophagy and apoptosis via activation of mTOR signalling. J Cell Mol Med. 2016;20:1908–19.
Yu J, Wang L, Akinyi M, Li Y, Duan Z, Zhu Y, et al. Danshensu protects isolated heart against ischemia reperfusion injury through activation of Akt/ERK1/2/Nrf2 signaling. Int J Clin Exp Med. 2015;8:14793–804.
Yin Y, Guan Y, Duan J, Wei G, Zhu Y, Quan W, et al. Cardioprotective effect of Danshensu against myocardial ischemia/reperfusion injury and inhibits apoptosis of H9c2 cardiomyocytes via Akt and ERK1/2 phosphorylation. Eur J Pharmacol. 2013;699:219–26.
Dey D, Han L, Bauer M, Sanada F, Oikonomopoulos A, Hosoda T, et al. Dissecting the molecular relationship among various cardiogenic progenitor cells. Circ Res. 2013;112:1253–62.
Eyre DR, Wu J. Collagen cross-links. Top Curr Chem. 2005;247:207–29.
Díez J, López B, González A, Querejeta R. The Role of myocardial collagen network in hypertensive heart disease. Curr Hypertens Rev. 2007;3:1–7.
Wang J, Huang W, Xu R, Nie Y, Cao X, Meng J, et al. MicroRNA-24 regulates cardiac fibrosis after myocardial infarction. J Cell Mol Med. 2012;16:2150–60.
Kaludercic N, Mialet-Perez J, Paolocci N, Parini A, Di Lisa F. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol. 2014;73:34–42.
Cederholm A, Frostegard J. Annexin A5 in cardiovascular disease and systemic lupus erythematosus. Immunobiology. 2005;210:761–8.
Wang RS, Loscalzo J. Illuminating drug action by network integration of disease genes: a case study of myocardial infarction. Mol Biosyst. 2016;12:1653–66.
Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol. 2009;9:62–70.
Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, et al. Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med. 2008;205:295–303.
Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007;13:962–9.
Iekushi K, Taniyama Y, Azuma J, Katsuragi N, Dosaka N, Sanada F, et al. Novel mechanisms of valsartan on the treatment of acute myocardial infarction through inhibition of the antiadhesion molecule periostin. Hypertension. 2007;49:1409–14.
Bouzeghrane F, Reinhardt DP, Reudelhuber TL, Thibault G. Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis. Am J Physiol Heart Circ Physiol. 2005;289:H982–91.
van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA. 2008;105:13027–32.
Nakayama T, Soma M, Saito S, Honye J, Yajima J, Rahmutula D, et al. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction. Am Heart J. 2002;143:797–801.
Friede KA, Ginsburg GS, Voora D. Gene expression signatures and the spectrum of coronary artery disease. J Cardiovasc Transl Res. 2015;8:339–52.
Wang R, Su C, Wang X, Fu Q, Gao X, Zhang C, et al. Global gene expression analysis combined with a genomics approach for the identification of signal transduction networks involved in postnatal mouse myocardial proliferation and development. Int J Mol Med. 2018;41:311–21.
Kim JJ, Park YM, Yoon D, Lee KY, Seob Song M, Doo Lee H, et al. Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. J Hum Genet. 2013;58:521–5.
Zhang Q, Timofeyev V, Lu L, Li N, Singapuri A, Long MK, et al. Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes. Circ Res. 2008;102:465–71.
Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, et al. TAp63 is important for cardiac differentiation of embryonic stem cells and heart development. Stem Cells. 2011;29:1672–83.
Senoo M, Pinto F, Crum CP, McKeon F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007;129:523–36.
Kanu N, Zhang T, Burrell RA, Chakraborty A, Cronshaw J, DaCosta C, et al. RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress. Oncogene. 2016;35:4020.
Yan S, Sorrell M, Berman Z. Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci. 2014;71:3951–67.
Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773:642–52.
Garin J, Diez R, Kieffer S, Dermine JF, Duclos S, Gagnon E, et al. The phagosome proteome: insight into phagosome functions. J Cell Biol. 2001;152:165–80.
Lavandero S, Troncoso R, Rothermel BA, Martinet W, Sadoshima J, Hill JA. Cardiovascular autophagy: concepts, controversies, and perspectives. Autophagy. 2013;9:1455–66.
Vadali K, Cai X, Schaller MD. Focal adhesion kinase: an essential kinase in the regulation of cardiovascular functions. IUBMB Life. 2007;59:709–16.
Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17:564–80.
Muslin AJ. MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond). 2008;115:203–18.
Cohen ED, Tian Y, Morrisey EE. Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal. Development. 2008;135:789–98.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81503039, 81573396, and 81773683) and the Discipline Leader Training Program of Pudong New Area Health System of Shanghai (PWRd2014-11). D.J. would like to give special thanks to the BGI-Shenzhen Corporation for its help in the experiments.
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CZ, JH, ZYZ, CZZ, YQ, and DJ designed the experiments; DJ, CZZ, YQ, and XFC performed the experiments and analyzed the data; DJ, YQ, and LJ wrote the manuscript; and CZ, JH, ZYZ, YFC, and AFC reviewed the manuscript.
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Jia, D., Zhang, Cz., Qiu, Y. et al. Cardioprotective mechanisms of salvianic acid A sodium in rats with myocardial infarction based on proteome and transcriptome analysis. Acta Pharmacol Sin 40, 1513–1522 (2019). https://doi.org/10.1038/s41401-019-0265-1
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DOI: https://doi.org/10.1038/s41401-019-0265-1
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