DL-3-n-butylphthalide improves ventricular function, and prevents ventricular remodeling and arrhythmias in post-MI rats

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Abstract

DL-3-n-butylphthalide (NBP) is used in the treatment of ischemic stroke. It was demonstrated NBP also has a cardioprotective effect in acute myocardial infarction (MI) model. However, the chronic effects of NBP on ventricular function, remodeling, and arrhythmias in post-MI stage are unknown. This study was to investigate the effect of NBP on reducing ventricular remodeling and arrhythmias in post-MI stage. Post-MI rats were randomly treated with 100 mg/kg NBP daily (n = 21) or vehicle (n = 21) for 5 weeks. Sham-operated rats were treated with the same dose vehicle (n = 18). Echocardiographic assessment, ventricular arrhythmias inducibility test, morphological and collagen analysis, immunohistochemistry, and western blot were studied. NBP significantly improved cardiac function, inhibited the severity and inducibility of ventricular arrhythmias, reduced cardiac index, fibrosis and hypertrophy, improved the protein expression and distribution of Cx43 gap junction, and upregulated PI3k/Akt/Nrf2 pathway and the downstream antioxidant response elements (ARE), including heme oxygenase-1, Glutathione, Cu-Zn superoxide dismutase, and Fe/Mn superoxide dismutase. These results suggest NBP improves LV function and reduces ventricular arrhythmias by mitigating LV fibrosis, hypertrophy, and Cx43 gap junction remodeling. PI3k/Akt/Nrf2/ARE signaling pathway may contribute to its anti-ventricular remodeling effects.

Keywords

DL-3-n-butylphthalide Ventricular remodeling Connexin43 Nrf2 
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Notes

Author contributions

The conception and design were proposed by Chunhua Ding. Animal experiment was finished by Huiliang Qiu, Jin Ma. Molecular biology experiments, data collection, and analysis were mainly conducted by Huiliang Qiu. Paper was drafted by Huiliang Qiu and reviewed by Chunhua Ding.

Compliance with ethical standards

Ethics

Animal experiments in this study were performed in accordance with standards issued by the State Committee of Science and Technology of the People’s Republic of China and was approved by the Animal Care Committee of Guangdong Provincial Hospital of Chinese Medicine.

References

  1. Anuja GI, Shine VJ, Latha PG, Suja SR (2017) Protective effect of ethyl acetate fraction of Drynaria quercifolia against CCl4 induced rat liver fibrosis via Nrf2/ARE and NFκB signalling pathway. J Ethnopharmacol. Nov 23. pii: S0378–8741(17)32525–4Google Scholar
  2. de Bakker JM, Coronel R, Tasseron S, Wilde AA, Opthof T, Janse MJ, van Capelle FJ, Becker AE, Jambroes G (1990) Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 15(7):1594–1607CrossRefPubMedGoogle Scholar
  3. Chen Z, Xie X, Huang J, Gong W, Zhu X, Chen Q, Huang J, Huang H (2017) Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-β1 via Nrf2/ARE pathway in glomerular mesangial cells. Free Radic Biol Med 102:77–86CrossRefPubMedGoogle Scholar
  4. Giepmans BN (2004) Gap junctions and connexin-interacting proteins. Cardiovasc Res 62:233–245CrossRefPubMedGoogle Scholar
  5. Jongsma HJ, Wilders R (2000) Gap junctions in cardiovascular disease. Circ Res 86(12):1193–1197CrossRefPubMedGoogle Scholar
  6. Lee KW, Everett TH 4th, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE (2006) Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation 114(16):1703–1712CrossRefPubMedCentralPubMedGoogle Scholar
  7. Lee TM, Lin SZ, Chang NC (2014) Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling. Free Radic Biol Med 77:71–81CrossRefPubMedGoogle Scholar
  8. Lerner DL, Yamada KA, Schuessler RB, Saffitz JE (2000) Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101:547–552CrossRefPubMedGoogle Scholar
  9. Li J, Li Y, Ogle M, Zhou X, Song M, Yu SP, Wei L (2010) DL-3-n-butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathway. Brain Res 1359:216–226CrossRefPubMedCentralPubMedGoogle Scholar
  10. Li J, Zhang C, Xing Y, Janicki JS, Yamamoto M, Wang XL, Tang DQ, Cui T (2011) Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. Cardiovasc Res 90(2):315–324CrossRefPubMedGoogle Scholar
  11. Ma S, Xu S, Liu B, Li J, Feng N, Wang L, Wang X (2009) Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats. Naunyn Schmiedeberg’s Arch Pharmacol 379(6):565–574CrossRefGoogle Scholar
  12. Münzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC (2017) Impact of oxidative stress on the heart and vasculature: part 2 of a 3-Part Series. J Am Coll Cardiol 70(2):212–229CrossRefPubMedGoogle Scholar
  13. Ng FS, Kalindjian JM, Cooper SA, Chowdhury RA, Patel PM, Dupont E, Lyon AR, Peters NS (2016) Enhancement of gap junction function during acute myocardial infarction modifies healing and reduces late ventricular arrhythmia susceptibility. JACC Clin Electrophysiol 2(5):574–582CrossRefPubMedCentralPubMedGoogle Scholar
  14. Nguyen T, El Salibi E, Rouleau JL (1998) Postinfarction survival and inducibility of ventricular arrhythmias in the spontaneously hypertensive rat : effects of ramipril and hydralazine. Circulation 98(19):2074–2080CrossRefPubMedGoogle Scholar
  15. Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE (2010) Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm 7(10):1438–1445CrossRefPubMedGoogle Scholar
  16. Osbourne A, Calway T, Broman M, McSharry S, Earley J, Kim GH (2014) Downregulation of connexin43 by microRNA-130a in cardiomyocytes results in cardiac arrhythmias. J Mol Cell Cardiol 74:53–63CrossRefPubMedCentralPubMedGoogle Scholar
  17. Peters NS (1996) New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin Sci (Lond) 90(6):447–452CrossRefGoogle Scholar
  18. Peters NS, Green CR, Poole-Wilson PA, Severs NJ (1993) Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88(3):864–875CrossRefPubMedGoogle Scholar
  19. Purnomo Y, Piccart Y, Coenen T, Prihadi JS, Lijnen PJ (2013) Oxidative stress and transforming growth factor-β1-induced cardiac fibrosis. Cardiovasc Hematol Disord Drug Targets 13(2):165–172CrossRefPubMedGoogle Scholar
  20. Qiu H, Wu H, Ma J, Cao H, Huang L, Qiu W, Peng Y, Ding C (2018) DL-3-n-butylphthalide reduces atrial fibrillation susceptibility by inhibiting atrial structural remodeling in rats with heart failure. Naunyn Schmiedeberg's Arch Pharmacol 391(3):323–334CrossRefGoogle Scholar
  21. Sovari AA, Rutledge CA, Jeong EM, Dolmatova E, Arasu D, Liu H, Vahdani N, Gu L, Zandieh S, Xiao L, Bonini MG, Duffy HS, Dudley SC Jr (2013) Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ Arrhythm Electrophysiol 6(3):623–631CrossRefPubMedCentralPubMedGoogle Scholar
  22. Tian X, He W, Yang R, Liu Y (2017) Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis. J Biomed Sci 24(1):38CrossRefPubMedCentralPubMedGoogle Scholar
  23. Wagner S, Rokita AG, Anderson ME, Maier LS (2013) Redox regulation of sodium and calcium handling. Antioxid Redox Signal 18:1063–1077CrossRefPubMedCentralPubMedGoogle Scholar
  24. Wang YG, Li Y, Wang CY, Ai JW, Dong XY, Huang HY, Feng ZY, Pan YM, Lin Y, Wang BX, Yao LL (2014) L-3-n-Butylphthalide protects rats' cardiomyocytes from ischaemia/reperfusion-induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol (Oxf). Mar;210(3):524–33Google Scholar
  25. Wang W, Li S, Wang H, Li B, Shao L, Lai Y, Horvath G, Wang Q, Yamamoto M, Janicki JS, Wang XL, Tang D, Cui T (2014b) Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. J Mol Cell Cardiol 72:305–315CrossRefPubMedCentralPubMedGoogle Scholar
  26. Wang CY, Wang ZY, Xie JW, Wang T, Wang X, Xu Y, Cai JH (2016a) Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer's disease mouse model. Neurobiol Aging 38:32–46CrossRefPubMedGoogle Scholar
  27. Wang F, Ma J, Han F, Guo X, Meng L, Sun Y, Jin C, Duan H, Li H, Peng Y (2016b) DL-3-n-butylphthalide delays the onset and progression of diabetic cataract by inhibiting oxidative stress in rat diabetic model. Sci Rep 6:19396CrossRefPubMedCentralPubMedGoogle Scholar
  28. Xiong N, Huang J, Chen C, Zhao Y, Zhang Z, Jia M, Zhang Z, Hou L, Yang H, Cao X, Liang Z, Zhang Y, Sun S, Lin Z, Wang T (2012) Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson's disease. Neurobiol Aging 33(8):1777–1791CrossRefPubMedGoogle Scholar
  29. Yeh YH, Kuo CT, Chang GJ, Chen YH, Lai YJ, Cheng ML, Chen WJ (2015) Rosuvastatin suppresses atrial tachycardia-induced cellular remodeling via Akt/Nrf2/heme oxygenase-1 pathway. J Mol Cell Cardiol 82:84–92CrossRefPubMedGoogle Scholar
  30. Zhao Y, Lee JH, Chen D, Gu X, Caslin A, Li J, Yu SP, Wei L (2017) DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice. Neurochem Int 111:82–92CrossRefPubMedGoogle Scholar
  31. Zhu J, Zhang Y, Yang C (2015) Protective effect of 3-n-butylphthalide against hypertensive nephropathy in spontaneously hypertensive rats. Mol Med Rep 11(2):1448–1454CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Second Clinical Medical CollegeGuangzhou University of Chinese MedicineGuangzhouChina
  2. 2.Cardiac DepartmentGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
  3. 3.Beijing University of Chinese MedicineBeijingChina
  4. 4.Cardiac DepartmentAerospace Center Hospital, Peking University Aerospace Clinical College of MedicineBeijingChina

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