DL-3-n-butylphthalide improves ventricular function, and prevents ventricular remodeling and arrhythmias in post-MI rats
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.
KeywordsDL-3-n-butylphthalide Ventricular remodeling Connexin43 Nrf2
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.
This study is supported by Guangdong Province Talents Project in Colleges and Universities (No. 2050205, Chunhua Ding) and Joint research project of Guangdong Provincial Department of Science and Technology & Guangdong Provincial Academy of Chinese Medicine (No.2014A020221045, Shen Huang).
Compliance with ethical standards
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.
- 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
- 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
- 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):574–582CrossRefPubMedPubMedCentralGoogle Scholar
- 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):623–631CrossRefPubMedPubMedCentralGoogle Scholar
- 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
- 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