Apigenin attenuates myocardial infarction-induced cardiomyocyte injury by modulating Parkin-mediated mitochondrial autophagy

Abstract

We aimed to detect whether the effect of apigenin (Apig) on the myocardial infarction-induced cardiomyocyte injury of mouse myocardial cells and acute myocardial infarction (AMI) mice was through regulating Parkin expression via miR-103-1-5p. The myocardial infarction cardiomyocyte model (Hypoxia/reoxygenation) was first constructed, then the mouse myocardial cells were treated with Apig, and the expression of miR-103-1-5p was decreased and the expression of Parkin was increased by qRT-PCR and Western blot. It was confirmed by miRNA pulldown and luciferase reporter system that miR-103-1-5p in mouse myocardial cells can bind to Parkin mRNA and inhibit Parkin expression. Next, a lentiviral vector silenced Parkin and overexpressing miR-103-1-5p was constructed and transfected into Apig-treated cells. Autophagy was detected by mitochondrial autophagy marker proteins [atypical protein kinase C (aPKC)-interacting protein (p62) and bcl-2/Adenovirus E1B 19-kd interacting protein 3 (BNIP3)] via Western blot, mitochondrial function was detected by JC-1 probe, and apoptosis was detected by flow cytometry. It was confirmed that Apig regulated mitochondria autophagy through miR-103-1-5p and Parkin, which ultimately affected cardiomyocyte death. Finally, an AMI mouse model was constructed, and then the mice were treated with Apig. The infarct size was detected by triphenyl tetrazolium chloride (TTC) staining, and the Apig relieved the myocardial infarction. The expression of miR-103-1-5p was decreased and the expression of Parkin was increased by qRT-PCR and Western blot. The above results simplified that the cardio protection of Apig and miR-103-1-5p against injury of myocardial infarction cardiomyocyte by targeting Parkin. These results provided a novel treatment against myocardial infarction cardiomyocyte.

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Abbreviations

3′-UTR:

3′ non-coding region

AMI:

acute myocardial infarction

Apig:

apigenin

aPKC:

atypical protein kinase C

BNIP3:

bcl-2/Adenovirus E1B 19-kd interacting protein 3

FCM:

flow cytometry assay

miRNA:

microRNA

MMP:

mitochondrial membrane potential

MUT:

mutant

SD:

standard deviation

TTC:

triphenyl tetrazolium chloride

WT:

wild-type

References

  1. Anversa P, Cheng W, Liu Y, Leri A, Redaelli G and Kajstura J 1998 Apoptosis and myocardial infarction. Basic Res Cardiol. 93 8–12

    Article  Google Scholar 

  2. Asche CV, Ren J, Kirkness CS, Kim M and Hippler S 2016 A prediction model to identify acute myocardial infarction (AMI) patients at risk for 30-day readmission. J. Am. Heart Assn. 7 e008882–e008892

    Google Scholar 

  3. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, et al. 2009 Chapter 12 monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 452 181–197

    Article  Google Scholar 

  4. Chang C, Lan K, Huang W, Lee Y, Lee T-W, et al. 2017 188Re-Liposome can induce mitochondrial autophagy and reverse drug resistance for ovarian cancer: from bench evidence to preliminary clinical proof-of-concept. Int. J. Mol. Sci. 18 903–918

    Article  Google Scholar 

  5. Choi AY, Ji HC, Lee JY, Yoon KS and Kang I 2010 Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. Neurochem. Int. 57 143–152

    CAS  Article  Google Scholar 

  6. Du H, Hao J, Liu F, Lu J and Yang X 2015 Apigenin attenuates acute myocardial infarction of rats via the inhibitions of matrix metalloprotease-9 and inflammatory reactions. Int J Clin Exp Med. 8 8854–8859

    PubMed  PubMed Central  Google Scholar 

  7. Dubrow R, Burnett CA, Gute DM and Brockert JE 1988 Ischemic heart disease and acute myocardial infarction mortality among police officers. J. Occupational Med. 30 650–654

    CAS  Article  Google Scholar 

  8. Durga Devi T, Babu M, Makinen P, Kaikkonen M, Heinaniemi M, et al. 2017 Aggravated post-infarct heart failure in type 2 diabetes is associated with impaired mitophagy and exaggerated inflammasome activation. Am. J. Pathol. 187 2659–2673

    CAS  Article  Google Scholar 

  9. Eiyama A and Okamoto K 2015 PINK1/Parkin-mediated mitophagy in mammalian cells. Curr. Opin. Cell Biol. 33 95–101

    CAS  Article  Google Scholar 

  10. Feistritzer HJ, Klug G, Reinstadler SJ, Mair J, Seidner B, et al. 2015 Aortic stiffness is associated with elevated high-sensitivity cardiac troponin T concentrations at a chronic stage after ST-segment elevation myocardial infarction. J. Hypertension 33 1970–1976

    CAS  Article  Google Scholar 

  11. Folts JD 1983 Severe myocardial ischemia and impaired contractile function caused by acute occlusive platelet thrombi in stenosed coronary arteries. J. Mol. Cell. Cardiol. 15 3

    Article  Google Scholar 

  12. Geisler S, Holmstrm KM, Skujat D, Fiesel FC, Rothfuss OC, et al. 2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12 119–131

    CAS  Article  Google Scholar 

  13. Ginwala R, McTish E, Raman C, Singh N, Nagarkatti M, et al. 2016 Apigenin, a natural flavonoid, attenuates EAE severity through the modulation of dendritic cell and other immune cell functions. J. Neuroimmune Pharmacol. 11 36–47

    Article  Google Scholar 

  14. Heikaus S, Berg LVD, Kempf T, Mahotka C, Gabbert HE, et al. 2016 HA14-1 is able to reconstitute the impaired mitochondrial pathway of apoptosis in renal cell carcinoma cell lines. Cell Oncol. 30 419–433

    Google Scholar 

  15. Hsieh C, Pai P, Hsueh H, Yuan S and Hsieh Y 2011 Complete induction of autophagy is essential for cardioprotection in sepsis. Annal. Surgery 253 1190–1200

    Article  Google Scholar 

  16. Huang L, Li L, Chen X, Zhang H and Shi Z 2013 MiR-103a targeting Piezo1 is involved in acute myocardial infarction through regulating endothelium function. Cardiol. J. 23 556–562

    Google Scholar 

  17. Kanamori H, Takemura G, Goto K, Maruyama R, Ono K, et al. 2011 Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am. J. Physiol. Heart Circulatory Physiol. 300 2261–2271

    Article  Google Scholar 

  18. Kfirerenfeld S, Haggiag N, Biton M, Stepensky P, Assayagasherie N, et al. 2016 miR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis. Oncotarget 8 472–489

    Article  Google Scholar 

  19. Lin M, Lu S, Wang A, Qi X, Zhao D, et al. 2011 Apigenin attenuates dopamine-induced apoptosis in melanocytes via oxidative stress-related p38, c-Jun NH2-terminal kinase and Akt signaling. J. Dermatol. Sci. 63 10–16

    CAS  Article  Google Scholar 

  20. Mao K, Wang K, Liu X and Klionsky DJ 2013 The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev. Cell 26 9–18

    CAS  Article  Google Scholar 

  21. Moe GW and José MG 2016 Role of cell death in the progression of heart failure. Heart Failure Rev. 21 157–167

    Article  Google Scholar 

  22. Na LI, Wen-Jun YU, Jia HB, Wang JX, Cong-Ye LI, et al. 2015 The protective role of parkin mediated mitophagy in a mouse model of type 1 diabetes combined with acute myocardial infarction. Progress Modern Biomed. 5 6201–6205

    Google Scholar 

  23. Poole AC, Thomas RE, Andrews LA, McBride HM and Pallanck LJ 2008 The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Nat. Acad. Sci. 105 1638–1643

    CAS  Article  Google Scholar 

  24. Studer M, Zuber M, Jamshidi P, Buser P and Erne P 2012 Thromboembolic acute myocardial infarction in a congenital double chambered left ventricle. Indian Heart J. 63 289–290

    Google Scholar 

  25. Tsuchiya Y 2006 MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res. 66 9090–9098

    CAS  Article  Google Scholar 

  26. Wang KS, Ma J, Mi C, Li J and Jin X 2016 Kamebakaurin inhibits the expression of hypoxia-inducible factor-1 and its target genes to confer antitumor activity. Oncol. Rep. 35 2045–2052

    CAS  Article  Google Scholar 

  27. Wang Y, Xu Y, Yin L, Xu L, Peng J et al. 2013 Synergistic anti-glioma effect of Hydroxygenkwanin and Apigenin in vitro. Chemico-Biol. Interact. 206 346–355

    CAS  Article  Google Scholar 

  28. Weng L, Guo X, Li Y, Yang X and Han Y 2016 Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice. Eur. J. Pharmacol. 774 50–54

    CAS  Article  Google Scholar 

  29. Wilfred BR, Wang W and Peter TN 2007 Energizing miRNA research: A review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol. Genet. Metab. 91 209–217

    CAS  Article  Google Scholar 

  30. Yang X, Yang J, Hu J, Li X, Zhang X, et al. 2015 Apigenin attenuates myocardial ischemia/reperfusion injury via the inactivation of p38 mitogen‑activated protein kinase. Mol. Med. Rep. 12 6873–6878

    CAS  Article  Google Scholar 

  31. Zang QS, Wolf SE and Minei JP 2014 Sepsis-induced cardiac mitochondrial damage and potential therapeutic interventions in the elderly. Aging Dis. 5 137–149

    PubMed  PubMed Central  Google Scholar 

  32. Zhang J, Zhao X, Zhu H, Wang J, Ma J et al. 2019 Apigenin protects against renal tubular epithelial cell injury and oxidative stress by high glucose via regulation of NF-E2-related factor 2 (Nrf2) pathway. Med. Sci. Monit. 25 5280–5288

    CAS  Article  Google Scholar 

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Correspondence to Dingli Xu.

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Corresponding editor: BJ Rao

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Wang, Z., Zhang, H., Liu, Z. et al. Apigenin attenuates myocardial infarction-induced cardiomyocyte injury by modulating Parkin-mediated mitochondrial autophagy. J Biosci 45, 75 (2020). https://doi.org/10.1007/s12038-020-00047-0

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Keywords

  • Apigenin
  • cardiomyocyte injury
  • microRNA-103-1-5p
  • mitochondrial autophagy
  • myocardial infarction
  • Parkin