DOI QR코드

DOI QR Code

Beneficial effects of andrographolide in a rat model of autoimmune myocarditis and its effects on PI3K/Akt pathway

  • Zhang, Qi (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease) ;
  • Hu, Li-qun (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease) ;
  • Li, Hong-qi (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease) ;
  • Wu, Jun (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease) ;
  • Bian, Na-na (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease) ;
  • Yan, Guang (Department of Geriatrics, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Anhui Institute of Cardiovascular Disease)
  • Received : 2018.04.16
  • Accepted : 2018.07.20
  • Published : 2019.03.01

Abstract

The study is to investigate effects of andrographolide on experimental autoimmune myocarditis (EAM). Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. The EAM rats were treated with either andrographolide (25, 50, 100 mg/kg/day) or vehicle for 21 days. An antigen-specific splenocytes proliferation assay was performed by using the cells from control rats immunized with cardiac myosin. Survival rates, myocardial pathology and myocardial functional parameters (left ventricle end-diastolic pressure, ${\pm}dP/dt$ and left ventricular internal dimension) of EAM rats received andrographolide were significantly improved. Andrographolide treatment caused an decrease in the infiltration of $CD3^+$ and $CD14^+$ positive cells in myocardial tissue. Moreover, andrographolide treatment caused a reduction in the plasma levels of tumor necrosis factor-alpha, interleukin-17 (IL-17) and myosin-antibody, and an increase in the level of IL-10 in EAM rats. Oral administration of andrographolide resulted in the decreased expression of p-PI3K, p-Akt without any change of PI3K and Akt. Further results indicate andrographolide significantly inhibited myosin-induced proliferation in splenocytes, and this effect was inhibited by co-treatment of SC79 (Akt activator). Our data indicate andrographolide inhibits development of EAM, and this beneficial effect may be due to powerful anti-inflammatory activity and inhibitory effect on PI3K/Akt pathway.

Keywords

References

  1. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, Kramer MR. Sudden unexpected death in persons less than 40 years of age. Am J Cardiol. 1991;68:1388-1392. https://doi.org/10.1016/0002-9149(91)90251-F
  2. Cooper LT Jr, Keren A, Sliwa K, Matsumori A, Mensah GA. The global burden of myocarditis: part 1: a systematic literature review for the global burden of diseases, injuries, and risk factors 2010 study. Glob Heart. 2014;9:121-129. https://doi.org/10.1016/j.gheart.2014.01.007
  3. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet. 2012;379:738-747. https://doi.org/10.1016/S0140-6736(11)60648-X
  4. Elamm C, Fairweather D, Cooper LT. Pathogenesis and diagnosis of myocarditis. Heart. 2012;11:835-840.
  5. Ghigo A, Li M. Phosphoinositide 3-kinase: friend and foe in cardiovascular disease. Front Pharmacol. 2015;6:169. https://doi.org/10.3389/fphar.2015.00169
  6. Yu P, Zhang Y, Li C, Li Y, Jiang S, Zhang X, Ding Z, Tu F, Wu J, Gao X, Li L. Class III PI3K- mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure. J Cell Mol Med. 2015;19:1710-1719. https://doi.org/10.1111/jcmm.12547
  7. Liu HS, Zhang J, Guo JL, Lin CY, Wang ZW. Phosphoinositide 3-kinase inhibitor LY294002 ameliorates the severity of myosin-induced myocarditis in mice. Curr Res Transl Med. 2016;64:21-27. https://doi.org/10.1016/j.retram.2016.01.012
  8. Lim JC, Chan TK, Ng DS, Sagineedu SR, Stanslas J, Wong WS. Andrographolide and its analogues: versatile bioactive molecules for combating inflammation and cancer. Clin Exp Pharmacol Physiol. 2012;39:300-310. https://doi.org/10.1111/j.1440-1681.2011.05633.x
  9. He CL, Yi PF, Fan QJ, Shen HQ, Jiang XL, Qin QQ, Song Z, Zhang C, Wu SC, Wei XB, Li YL, Fu BD. Xiang-Qi-Tang and its active components exhibit anti-inflammatory and anticoagulant properties by inhibiting MAPK and NF-${\kappa}B$ signaling pathways in LPS-treated rat cardiac microvascular endothelial cells. Immunopharmacol Immunotoxicol. 2013;35:215-224. https://doi.org/10.3109/08923973.2012.744034
  10. Hsieh YL, Shibu MA, Lii CK, Viswanadha VP, Lin YL, Lai CH, Chen YF, Lin KH, Kuo WW, Huang CY. Andrographis paniculata extract attenuates pathological cardiac hypertrophy and apoptosis in high-fat diet fed mice. J Ethnopharmacol. 2016;192:170-177. https://doi.org/10.1016/j.jep.2016.07.018
  11. Lee YC, Lin HH, Hsu CH, Wang CJ, Chiang TA, Chen JH. Inhibitory effects of andrographolide on migration and invasion in human non-small cell lung cancer A549 cells via down-regulation of PI3K/Akt signaling pathway. Eur J Pharmacol. 2010;632:23-32. https://doi.org/10.1016/j.ejphar.2010.01.009
  12. Wang W, Wang J, Dong SF, Liu CH, Italiani P, Sun SH, Xu J, Boraschi D, Ma SP, Qu D. Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response. Acta Pharmacol Sin. 2010;31:191-201. https://doi.org/10.1038/aps.2009.205
  13. Veeraveedu PT, Watanabe K, Ma M, Thandavarayan RA, Palaniyandi SS, Yamaguchi K, Suzuki K, Kodama M, Aizawa Y. Comparative effects of torasemide and furosemide in rats with heart failure. Biochem Pharmacol. 2008;75:649-659. https://doi.org/10.1016/j.bcp.2007.09.026
  14. Liu X, Zhang X, Ye L, Yuan H. Protective mechanisms of berberine against experimental autoimmune myocarditis in a rat model. Biomed Pharmacother. 2016;79:222-230. https://doi.org/10.1016/j.biopha.2016.02.015
  15. Zhang J, Zhu D, Wang Y, Ju Y. Andrographolide attenuates LPSinduced cardiac malfunctions through inhibition of $I{\kappa}B$ phosphorylation and apoptosis in mice. Cell Physiol Biochem. 2015;37:1619-1628. https://doi.org/10.1159/000438528
  16. Woo AY, Waye MM, Tsui SK, Yeung ST, Cheng CH. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury. J Pharmacol Exp Ther. 2008;325:226-235. https://doi.org/10.1124/jpet.107.133918
  17. Lichtman AH. The heart of the matter: protection of the myocardium from T cells. J Autoimmun. 2013;45:90-96. https://doi.org/10.1016/j.jaut.2013.05.004
  18. Myers JM, Cooper LT, Kem DC, Stavrakis S, Kosanke SD, Shevach EM, Fairweather D, Stoner JA, Cox CJ, Cunningham MW. Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight. 2016;1(9):e85851.
  19. Liu Y, Zhu H, Su Z, Sun C, Yin J, Yuan H, Sandoghchian S, Jiao Z, Wang S, Xu H. IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a $PKC{\beta}$/Erk1/2/NF-${\kappa}B$-dependent signaling pathway. Int Immunol. 2012;24:605-612. https://doi.org/10.1093/intimm/dxs056
  20. Stumpf C, Seybold K, Petzi S, Wasmeier G, Raaz D, Yilmaz A, Anger T, Daniel WG, Garlichs CD. Interleukin-10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction. Eur J Heart Fail. 2008;10:733-739. https://doi.org/10.1016/j.ejheart.2008.06.007
  21. Yu Y, Zhang ZH, Wei SG, Chu Y, Weiss RM, Heistad DD, Felder RB. Central gene transfer of interleukin-10 reduces hypothalamic inflammation and evidence of heart failure in rats after myocardial infarction. Circ Res. 2007;101:304-312. https://doi.org/10.1161/CIRCRESAHA.107.148940
  22. Su SA, Yang D, Zhu W, Cai Z, Zhang N, Zhao L, Wang JA, Xiang M. Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway. Biochim Biophys Acta. 2016;1863:2784-2794. https://doi.org/10.1016/j.bbamcr.2016.08.013
  23. Damas JK, Aukrust P, Ueland T, Odegaard A, Eiken HG, Gullestad L, Sejersted OM, Christensen G. Monocyte chemoattractant protein-1 enhances and interleukin-10 suppresses the production of inflammatory cytokines in adult rat cardiomyocytes. Basic Res Cardiol. 2001;96:345-352. https://doi.org/10.1007/s003950170042
  24. Chen ZW, Qian JY, Ma JY, Chang SF, Yun H, Jin H, Sun AJ, Zou YZ, Ge JB. $TNF-{\alpha}$-induced cardiomyocyte apoptosis contributes to cardiac dysfunction after coronary microembolization in mini-pigs. J Cell Mol Med. 2014;18:1953-1963. https://doi.org/10.1111/jcmm.12342
  25. Duerrschmid C, Trial J, Wang Y, Entman ML, Haudek SB. Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis. Circ Heart Fail. 2015;8:352-361. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001893
  26. Guan SP, Kong LR, Cheng C, Lim JC, Wong WS. Protective role of 14-deoxy-11,12-didehydroandrographolide, a noncytotoxic analogue of andrographolide, in allergic airway inflammation. J Nat Prod. 2011;74:1484-1490. https://doi.org/10.1021/np2002572
  27. Ji X, Li C, Ou Y, Li N, Yuan K, Yang G, Chen X, Yang Z, Liu B, Cheung WW, Wang L, Huang R, Lan T. Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia- mediated renal oxidative stress and inflammation via Akt/NF-${\kappa}B$ pathway. Mol Cell Endocrinol. 2016;437:268-279. https://doi.org/10.1016/j.mce.2016.06.029
  28. Yin JN, Li YN, Gao Y, Li SB, Li JD. Andrographolide plays an important role in bleomycin-induced pulmonary fibrosis treatment. Int J Clin Exp Med. 2015;8:12374-12381.
  29. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A. 2002;99:12333-12338. https://doi.org/10.1073/pnas.172376399
  30. DeBosch B, Treskov I, Lupu TS, Weinheimer C, Kovacs A, Courtois M, Muslin AJ. Akt1 is required for physiological cardiac growth. Circulation. 2006;113:2097-2104. https://doi.org/10.1161/CIRCULATIONAHA.105.595231
  31. McMullen JR, Shioi T, Huang WY, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase($p110{\alpha}$) pathway. J Biol Chem. 2004;279:4782-4793. https://doi.org/10.1074/jbc.M310405200
  32. Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC, Izumo S.The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 2000;19:2537-2548. https://doi.org/10.1093/emboj/19.11.2537
  33. Shiojima I , Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005;115:2108-2118. https://doi.org/10.1172/JCI24682
  34. Chen HW, Lin AH, Chu HC, Li CC, Tsai CW, Chao CY, Wang CJ, Lii CK, Liu KL. Inhibition of $TNF-{\alpha}$-Induced inflammation by andrographolide via down-regulation of the PI3K/Akt signaling pathway. J Nat Prod. 2011;74:2408-2413. https://doi.org/10.1021/np200631v
  35. Lu CY, Yang YC, Li CC, Liu KL, Lii CK, Chen HW. Andrographolide inhibits $TNF{\alpha}$-induced ICAM-1 expression via suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression through the PI3K/Akt/Nrf2 and PI3K/Akt/AP-1 pathways in human endothelial cells. Biochem Pharmacol. 2014;91:40-50. https://doi.org/10.1016/j.bcp.2014.06.024

Cited by

  1. A review on the molecular basis underlying the protective effects of Andrographis paniculata and andrographolide against myocardial injury vol.15, 2019, https://doi.org/10.2147/dddt.s331027
  2. Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches vol.36, pp.1, 2022, https://doi.org/10.1002/ptr.7324