Alternation of heart microRNA-mRNA network by high-intensity interval training and proanthocyanidin in myocardial ischemia rats: Artificial intelligence and validation experimental
Safar Zarei
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Search for more papers by this authorCorresponding Author
Farzaneh Taghian
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Correspondence
Farzaneh Taghian, Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
Email: [email protected]; [email protected]
Search for more papers by this authorGholamreza Sharifi
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Search for more papers by this authorHassanali Abedi
Research Center for Noncommunicable Diseases, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
Search for more papers by this authorSafar Zarei
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Search for more papers by this authorCorresponding Author
Farzaneh Taghian
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Correspondence
Farzaneh Taghian, Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
Email: [email protected]; [email protected]
Search for more papers by this authorGholamreza Sharifi
Department of Sports Physiology, School of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
Search for more papers by this authorHassanali Abedi
Research Center for Noncommunicable Diseases, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
Search for more papers by this authorAbstract
Heart ischemia is an irreversible condition that occurs via decreased blood flow in vessels by genetic factors, molecular regulators, and environmental conditions. The microRNAs binding to 3´UTR of target genes can influence gene expression and play pivotal roles in several mechanisms identified as a potential biomarker to the pathogenesis. We have screened a pool of microRNAs and mRNAs according to their potential correlation to myocardial ischemia based on artificial intelligence. We constructed the hub genes and mRNA-microRNA networks by R programing language and in silico analysis. Moreover, we calculated the binding affinity of the 3D structure of proanthocyanidin on VEGFα and GATA4 to ameliorate heart tissue after ischemia. Then we treated rats with 300 mg/kg proanthocyanidins and exercised in different intensity and duration times (low, moderate, and high-intensity interval training) for 14 weeks. In the second step, after 14 weeks, isoproterenol hydrochloride was injected into the rats, and myocardial ischemia was induced. We indicated that VEGFα, GATA4, and GJA1 axis associated with miR-27a-3p, miR-499-5p, miR-206-3p, miR-208a-3p are regulatable after 14 weeks of exercise training and proanthocyanidin extract consumption and could prevent myocardial injuries in ischemia. Moreover, we revealed different intensity and duration times, and proanthocyanidin modulated the microRNA-mRNA interaction in rats with myocardial ischemia. Proanthocyanidin consumption as a bioactive compound may significantly ameliorate myocardial dysfunction and offset pathological hallmarks of myocardial ischemia. Moreover, exercise has protective effects on myocardial tissue by reprograming genes and genetic regulator factors.
Practical applications
Complimentary medicine identified Proanthocyanidin and exercise are recognized as effective methods to prevent and improve Myocardial ischemia. According to medical biology servers, we explored the VEGFα, GATA4, and GJA1 axis associated with miR-27a-3p, miR-499-5p, miR-206-3p, miR-208a-3p as a vital pathomechanism of myocardial ischemia. Furthermore, proanthocyanidin extract is the effective compound that could has protective effects on myocardial tissue by reprograming genes and genetic regulator factors. Furthermore, proanthocyanidin and swimming training might recover myocardial dysfunction and regulate the hub genes and mRNA-microRNA networks.
CONFLICT OF INTEREST
None of the authors has any conflicts of interest to disclose.
Open Research
DATA AVAILABILITY STATEMENT
All of the raw data and materials in the Islamic Azad University Isfahan (Khorasgan) branch are available upon request.
REFERENCES
- Agarwal, V., Bell, G. W., Nam, J.-W., & Bartel, D. P. (2015). Predicting effective microRNA target sites in mammalian mRNAs. eLife, 4, e05005.
- Albrecht-Schgoer, K., Schgoer, W., Holfeld, J., Theurl, M., Wiedemann, D., Steger, C., Gupta, R., Semsroth, S., Fischer-Colbrie, R., Beer, A. G. E., Stanzl, U., Huber, E., Misener, S., Dejaco, D., Kishore, R., Pachinger, O., Grimm, M., Bonaros, N., & Kirchmair, R. (2012). The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. Circulation, 126(21), 2491–2501.
- Angadi, S. S., Mookadam, F., Lee, C. D., Tucker, W. J., Haykowsky, M. J., & Gaesser, G. A. (2015). High-intensity interval training vs. moderate-intensity continuous exercise training in heart failure with preserved ejection fraction: A pilot study. Journal of Applied Physiology, 119(6), 753–758.
- Asbaghi, O., Nazarian, B., Reiner, Ž., Amirani, E., Kolahdooz, F., Chamani, M., & Asemi, Z. (2020). The effects of grape seed extract on glycemic control, serum lipoproteins, inflammation, and body weight: A systematic review and meta-analysis of randomized controlled trials. Phytotherapy Research, 34(2), 239–253.
- Basheer, W. A., Fu, Y., Shimura, D., Xiao, S., Agvanian, S., Hernandez, D. M., Hitzeman, T. C., Hong, T., & Shaw, R. M. (2018). Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury. JCI Insight, 3(20), 1–15.
- Belviranlı, M., Gökbel, H., Okudan, N., & Başaralı, K. (2012). Effects of grape seed extract supplementation on exercise-induced oxidative stress in rats. British Journal of Nutrition, 108(2), 249–256.
- Bhachoo, J., & Beuming, T. (2017). Investigating protein–peptide interactions using the Schrödinger computational suite. Modeling Peptide-Protein Interactions, 1561, 235–254.
- Boengler, K., Bulic, M., Schreckenberg, R., Schlüter, K. D., & Schulz, R. (2017). The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43. British Journal of Pharmacology, 174(13), 2060–2073.
- Braile, M., Marcella, S., Cristinziano, L., Galdiero, M. R., Modestino, L., Ferrara, A. L., Varricchi, G., Marone, G., & Loffredo, S. (2020). VEGF-A in cardiomyocytes and heart diseases. International Journal of Molecular Sciences, 21(15), 5294.
- Brennan, L. A., Morris, G. M., Wasson, G. R., Hannigan, B. M., & Barnett, Y. A. (2000). The effect of vitamin C or vitamin E supplementation on basal and H2O2-induced DNA damage in human lymphocytes. British Journal of Nutrition, 84(2), 195–202.
- Bu, D., Luo, H., Huo, P., Wang, Z., Zhang, S., He, Z., Wu, Y., Zhao, L., Liu, J., Guo, J., Fang, S., Cao, W., Yi, L., Zhao, Y., & Kong, L. (2021). KOBAS-i: Intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic Acids Research, 49, W317–W325.
- Burley, S. K., Bhikadiya, C., Bi, C., Bittrich, S., Chen, L., Crichlow, G. V., Christie, C. H., Dalenberg, K., Di Costanzo, L., Duarte, J. M., Dutta, S., Feng, Z., Ganesan, S., Goodsell, D. S., Ghosh, S., Green, R. K., Guranović, V., Guzenko, D., Hudson, B. P., … Zhuravleva, M. (2021). RCSB protein data bank: Powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Research, 49(D1), D437–D451.
- Cengiz, M., Karatas, O. F., Koparir, E., Yavuzer, S., Ali, C., Yavuzer, H., Kirat, E., Karter, Y., & Ozen, M. (2015). Differential expression of hypertension-associated microRNAs in the plasma of patients with white coat hypertension. Medicine, 94(13), e693.
- Chen, Y., & Wang, X. (2020). miRDB: An online database for prediction of functional microRNA targets. Nucleic Acids Research, 48(D1), D127–D131.
- Cheng, C., Li, P., Wang, Y., Bi, M., & Wu, P. (2016). Study on the expression of VEGF and HIF-1α in infarct area of rats with AMI. European Review for Medical and Pharmacological Sciences, 20(1), 115–119.
- Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 1–13.
- Dallakyan, S., & Olson, A. J. (2015). Small-molecule library screening by docking with PyRx. In J. E. Hempel (Ed.), Chemical biology (pp. 243–250). Springer.
10.1007/978-1-4939-2269-7_19 Google Scholar
- Du, J.-K., Cong, B.-H., Yu, Q., Wang, H., Wang, L., Wang, C.-N., Tang, X. L., Lu, J. Q., Zhu, X. Y., & Ni, X. (2016). Upregulation of microRNA-22 contributes to myocardial ischemia-reperfusion injury by interfering with the mitochondrial function. Free Radical Biology and Medicine, 96, 406–417.
- Farías, J. G., Molina, V. M., Carrasco, R. A., Zepeda, A. B., Figueroa, E., Letelier, P., & Castillo, R. L. (2017). Antioxidant therapeutic strategies for cardiovascular conditions associated with oxidative stress. Nutrients, 9(9), 966.
- Fernandes, T., Baraúna, V. G., Negrão, C. E., Phillips, M. I., & Oliveira, E. M. (2015). Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. American Journal of Physiology-Heart and Circulatory Physiology, 309(4), H543–H552.
- Fernández, K., Vega, M., & Aspé, E. (2015). An enzymatic extraction of proanthocyanidins from País grape seeds and skins. Food Chemistry, 168, 7–13.
- Fichtlscherer, S., De Rosa, S., Fox, H., Schwietz, T., Fischer, A., Liebetrau, C., Weber, M., Hamm, C. W., Röxe, T., Müller-Ardogan, M., Bonauer, A., Zeiher, A. M., & Dimmeler, S. (2010). Circulating microRNAs in patients with coronary artery disease. Circulation Research, 107(5), 677–684.
- French, J. P., Hamilton, K. L., Quindry, J. C., Lee, Y., Upchurch, P. A., & Powers, S. K. (2008). Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. The FASEB Journal, 22(8), 2862–2871.
- Frentzou, G. A., Drinkhill, M. J., Turner, N. A., Ball, S. G., & Ainscough, J. F. (2015). A state of reversible compensated ventricular dysfunction precedes pathological remodelling in response to cardiomyocyte-specific activity of angiotensin II type-1 receptor in mice. Disease Models & Mechanisms, 8(8), 783–794.
- Fu, Q., Lu, Z., Fu, X., Ma, S., & Lu, X. (2019). MicroRNA 27b promotes cardiac fibrosis by targeting the FBW7/Snail pathway. Aging (Albany NY), 11(24), 11865–11879.
- Griffiths, E. J., Ocampo, C. J., Savage, J. S., Rutter, G. A., Hansford, R. G., Stern, M. D., & Silverman, H. S. (1998). Mitochondrial calcium transporting pathways during hypoxia and reoxygenation in single rat cardiomyocytes. Cardiovascular Research, 39(2), 423–433.
- Hajibabaie, F., Kouhpayeh, S., Mirian, M., Rahimmanesh, I., Boshtam, M., Sadeghian, L., Gheibi, A., Khanahmad, H., & Shariati, L. (2020). MicroRNAs as the actors in the atherosclerosis scenario. Journal of Physiology and Biochemistry, 76(1), 1–12.
- Huang, G.-Y., Xie, L.-J., Linask, K. L., Zhang, C., Zhao, X.-Q., Yang, Y., Zhou, G.-M., Wu, Y.-J., Marquez-Rosado, L., McElhinney, D. B., Goldmuntz, E., Liu, C., Lampe, P. D., Chatterjee, B., & Lo, C. W. (2011). Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models. Journal of Cardiovascular Disease Research, 2(4), 206–212.
- Huang, Y. M., Li, W. W., Wu, J., Han, M., & Li, B. H. (2019). The diagnostic value of circulating microRNAs in heart failure. Experimental and Therapeutic Medicine, 17(3), 1985–2003.
- Jeyaseelan, K., Lim, K. Y., & Armugam, A. (2008). MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke, 39(3), 959–966.
- Jhun, J. Y., Moon, S.-J., Yoon, B. Y., Byun, J. K., Kim, E. K., Yang, E. J., Ju, J. H., Hong, Y. S., Min, J. K., Park, S. H., Kim, H. Y., & Cho, M.-L. (2013). Grape seed proanthocyanidin extract–mediated regulation of STAT3 proteins contributes to treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis. PLoS One, 8(11), e78843.
- Karthick, M., & Prince, P. S. M. (2006). Preventive effect of rutin, a bioflavonoid, on lipid peroxides and antioxidants in isoproterenol-induced myocardial infarction in rats. Journal of Pharmacy and Pharmacology, 58(5), 701–707.
- Kovács, D., Palkovicsné Pézsa, N., Jerzsele, Á., Süth, M., & Farkas, O. (2022). Protective effects of grape seed oligomeric proanthocyanidins in IPEC-J2–Escherichia coli/Salmonella typhimurium co-culture. Antibiotics, 11(1), 110.
- Leptidis, S., El Azzouzi, H., Lok, S. I., de Weger, R., Olieslagers, S., Kisters, N., Silva, G. J., Heymans, S., Cuppen, E., Berezikov, E., De Windt, L. J., & da Costa Martins, P. (2013). A deep sequencing approach to uncover the miRNOME in the human heart. PLoS One, 8(2), e57800.
- Li, T., Yang, G.-M., Zhu, Y., Wu, Y., Chen, X.-Y., Lan, D., Tian, K.-L., & Liu, L.-M. (2015). Diabetes and hyperlipidemia induce dysfunction of VSMCs: Contribution of the metabolic inflammation/miRNA pathway. American Journal of Physiology-Endocrinology and Metabolism, 308(4), E257–E269.
- Lian, Y., Gao, L., Guo, P., Zhao, Y., & Lin, T. (2016). Grape seed proanthocyanidins extract prevents cisplatin-induced cardiotoxicity in rats. Food Science and Technology Research, 22(3), 403–408.
- Lobo Filho, H. G., Ferreira, N. L., Sousa, R. B. D., Carvalho, E. R. D., Lobo, P. L. D., & Lobo Filho, J. G. (2011). Experimental model of myocardial infarction induced by isoproterenol in rats. Brazilian Journal of Cardiovascular Surgery, 26, 469–476.
- Lv, S., Li, X., Zhao, S., Liu, H., & Wang, H. (2021). The role of the signaling pathways involved in the protective effect of exogenous hydrogen sulfide on myocardial ischemia-reperfusion injury. Frontiers in Cell and Developmental Biology, 2415.
- Mei-Ling, A. J., Koval, O. M., Li, J., He, B. J., Allamargot, C., Gao, Z., Luczak, E. D., Hall, D. D., Fink, B. D., Chen, B., Yang, J., Moore, S. A., Scholz, T. D., Strack, S., Mohler, P. J., Sivitz, W. I., Song, L.-S., & Anderson, M. E. (2012). CaMKII determines mitochondrial stress responses in heart. Nature, 491(7423), 269–273.
- Mosaddeghi, P., Eslami, M., Farahmandnejad, M., Akhavein, M., Ranjbarfarrokhi, R., Khorraminejad-Shirazi, M., Shahabinezhad, F., Taghipour, M., Dorvash, M., Sakhteman, A., Zarshenas, M. M., Nezafat, N., Mobasheri, M., & Ghasemi, Y. (2021). A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants. Scientific Reports, 11(1), 1–15.
- Murugesan, M., Revathi, R., & Manju, V. (2011). Cardioprotective effect of fenugreek on isoproterenol-induced myocardial infarction in rats. Indian Journal of Pharmacology, 43(5), 516–519.
- Nakano, Y., Matoba, T., Tokutome, M., Funamoto, D., Katsuki, S., Ikeda, G., Nagaoka, K., Ishikita, A., Nakano, K., Koga, J.-i., Sunagawa, K., & Egashira, K. (2016). Nanoparticle-mediated delivery of irbesartan induces cardioprotection from myocardial ischemia-reperfusion injury by antagonizing monocyte-mediated inflammation. Scientific Reports, 6(1), 1–14.
- Oliveros, J. C. (2007). VENNY. An interactive tool for comparing lists with Venn Diagrams. Scientific Research Publishing. http://bioinfogp.cnb.csic.es/tools/venny/index.html
- Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612.
- Rajadurai, M., & Prince, P. S. M. (2007). Preventive effect of naringin on isoproterenol-induced cardiotoxicity in Wistar rats: An in vivo and in vitro study. Toxicology, 232(3), 216–225.
- Rodríguez-Pérez, C., García-Villanova, B., Guerra-Hernández, E., & Verardo, V. (2019). Grape seeds proanthocyanidins: An overview of in vivo bioactivity in animal models. Nutrients, 11(10), 2435.
- Roncarati, R., Viviani Anselmi, C., Losi, M. A., Papa, L., Cavarretta, E., Da Costa Martins, P., Contaldi, C., Jotti, G. S., Franzone, A., Galastri, L., Latronico, M. V. G., Imbriaco, M., Esposito, G., De Windt, L., Betocchi, S., & Condorelli, G. (2014). Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 63(9), 920–927.
- Ruan, Y., Jin, Q., Zeng, J., Ren, F., Xie, Z., Ji, K., Wu, L., Wu, J., & Li, L. (2020). Grape seed proanthocyanidin extract ameliorates cardiac remodelling after myocardial infarction through PI3K/AKT pathway in mice. Frontiers in Pharmacology, 11, 2040.
- Rysä, J., Tenhunen, O., Serpi, R., Soini, Y., Nemer, M., Leskinen, H., & Ruskoaho, H. (2010). GATA-4 is an angiogenic survival factor of the infarcted heart. Circulation: Heart Failure, 3(3), 440–450.
- Seko, Y., Fukuda, S., & Nagai, R. (2004). Serum levels of endostatin, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with acute myocardial infarction undergoing early reperfusion therapy. Clinical Science, 106(5), 439–442.
- Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research, 13(11), 2498–2504.
- Sticht, C., De La Torre, C., Parveen, A., & Gretz, N. J. P. O. (2018). miRWalk: An online resource for prediction of microRNA binding sites. PloS One, 13(10), e0206239.
- Szklarczyk, D., Gable, A. L., Nastou, K. C., Lyon, D., Kirsch, R., Pyysalo, S., Doncheva, N. T., Legeay, M., Fang, T., Bork, P., Jensen, L. J., & von Mering, C. (2021). The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Research, 49(D1), D605–D612.
- Ueda, K., Takano, H., Niitsuma, Y., Hasegawa, H., Uchiyama, R., Oka, T., Miyazaki, M., Nakaya, H., & Komuro, I. (2010). Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice. The Journal of Clinical Investigation, 120(6), 2016–2029.
- Vlachos, I. S., Zagganas, K., Paraskevopoulou, M. D., Georgakilas, G., Karagkouni, D., Vergoulis, T., Dalamagas, T., & Hatzigeorgiou, A. G. (2015). DIANA-miRPath v3. 0: Deciphering microRNA function with experimental support. Nucleic Acids Research, 43(W1), W460–W466.
- Wai, T., García-Prieto, J., Baker, M. J., Merkwirth, C., Benit, P., Rustin, P., Rupérez, F. J., Barbas, C., Ibañez, B., & Langer, T. (2015). Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science, 350(6265), 1221–1232.
- Walters, A. M., Porter, G. A., Jr., & Brookes, P. S. (2012). Mitochondria as a drug target in ischemic heart disease and cardiomyopathy. Circulation Research, 111(9), 1222–1236.
- Wang, D., & Yan, C. (2022). MicroRNA-208a-3p participates in coronary heart disease by regulating the growth of hVSMCs by targeting BTG1. Experimental and Therapeutic Medicine, 23(1), 1–8.
- Wang, H., Bei, Y., Lu, Y., Sun, W., Liu, Q., Wang, Y., Cao, Y., Chen, P., Xiao, J., & Kong, X. (2015). Exercise prevents cardiac injury and improves mitochondrial biogenesis in advanced diabetic cardiomyopathy with PGC-1α and Akt activation. Cellular Physiology and Biochemistry, 35(6), 2159–2168.
- Waring, C. D., Vicinanza, C., Papalamprou, A., Smith, A. J., Purushothaman, S., Goldspink, D. F., Nadal-Ginard, B., Torella, D., & Ellison, G. M. (2014). The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. European Heart Journal, 35(39), 2722–2731.
- Xie, Z., Bailey, A., Kuleshov, M. V., Clarke, D. J., Evangelista, J. E., Jenkins, S. L., Lachmann, A., Wojciechowicz, M. L., Kropiwnicki, E., Jagodnik, K. M., Jeon, M., & Ma'ayan, A. (2021). Gene set knowledge discovery with Enrichr. Current Protocols, 1(3), e90.
- Yan, Y., Dang, H., Zhang, X., Wang, X., & Liu, X. (2020). The protective role of MiR-206 in regulating cardiomyocytes apoptosis induced by ischemic injury by targeting PTP1B. Bioscience Reports, 40(1), BSR20191000.
- Yang, Z., Wan, J., Pan, W., & Zou, J. (2018). Expression of vascular endothelial growth factor in cardiac repair: Signaling mechanisms mediating vascular protective effects. International Journal of Biological Macromolecules, 113, 179–185.
- Zhang, Q., Shang, M., Zhang, M., Wang, Y., Chen, Y., Wu, Y., Liu, M., Song, J., & Liu, Y. (2016). Microvesicles derived from hypoxia/reoxygenation-treated human umbilical vein endothelial cells promote apoptosis and oxidative stress in H9c2 cardiomyocytes. BMC Cell Biology, 17(1), 1–10.
- Zhang, Y., Li, H.-H., Yang, R., Yang, B.-J., & Gao, Z.-Y. (2017). Association between circulating microRNA-208a and severity of coronary heart disease. Scandinavian Journal of Clinical and Laboratory Investigation, 77(5), 379–384.
- Zhou, Y., Li, M., Song, J., Shi, Y., Qin, X., Gao, Z., Lv, Y., & Du, G. (2020). The cardioprotective effects of the new crystal form of puerarin in isoproterenol-induced myocardial ischemia rats based on metabolomics. Scientific Reports, 10(1), 1–18.
- Zhu, J., Yao, K., Wang, Q., Guo, J., Shi, H., Ma, L., Liu, H., Gao, W., Zou, Y., & Ge, J. (2016). Ischemic postconditioning-regulated miR-499 protects the rat heart against ischemia/reperfusion injury by inhibiting apoptosis through PDCD4. Cellular Physiology and Biochemistry, 39(6), 2364–2380.