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DOI: 10.1055/s-0043-118663
Aucubin Protects against TGFβ1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKα/mTOR Signaling Pathway
Publikationsverlauf
received 05. Mai 2017
revised 05. August 2017
accepted 16. August 2017
Publikationsdatum:
25. August 2017 (online)
![](https://www.thieme-connect.de/media/plantamedica/201802/lookinside/thumbnails/10-1055-s-0043-118663_pmb0392-1.jpg)
Abstract
Fibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 µM) followed by transforming growth factor β1 (TGFβ1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of α-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFβ1-induced proliferation in fibroblasts and inhibited the TGFβ1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKα inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFβ1-induced fibroblast proliferation, activation and function by regulating the AMPKα/mTOR signal axis.
* Yang Xiao and Wei Chang contribute to the work equally.
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References
- 1 Grimaldi V, De Pascale MR, Zullo A, Soricelli A, Infante T, Mancini FP, Napoli C. Evidence of epigenetic tags in cardiac fibrosis. J Cardiol 2017; 69: 401-408
- 2 Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation 2012; 125: 1795-1808
- 3 Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE. Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal 2012; 24: 1031-1036
- 4 Dzeshka MS, Lip GY, Snezhitskiy V, Shantsila E. Cardiac fibrosis in patients with atrial fibrillation: mechanisms and clinical implications. J Am Coll Cardiol 2015; 66: 943-959
- 5 Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res 2016; 118: 1021-1040
- 6 Ahamed J, Terry H, Choi ME, Laurence J. Transforming growth factor-beta1-mediated cardiac fibrosis: potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease. AIDS 2016; 30: 535-542
- 7 Lee GH, Lee MR, Lee HY, Kim SH, Kim HK, Kim HR, Chae HJ. Eucommia ulmoides cortex, geniposide and aucubin regulate lipotoxicity through the inhibition of lysosomal BAX. PLoS One 2014; 9: e88017
- 8 Wang SN, Xie GP, Qin CH, Chen YR, Zhang KR, Li X, Wu Q, Dong WQ, Yang J, Yu B. Aucubin prevents interleukin-1 beta induced inflammation and cartilage matrix degradation via inhibition of NF-kappaB signaling pathway in rat articular chondrocytes. Int Immunopharmacol 2015; 24: 408-415
- 9 Xue HY, Gao GZ, Lin QY, Jin LJ, Xu YP. Protective effects of aucubin on H2O2-induced apoptosis in PC12 cells. Phytother Res 2012; 26: 369-374
- 10 Xue HY, Jin L, Jin LJ, Li XY, Zhang P, Ma YS, Lu YN, Xia YQ, Xu YP. Aucubin prevents loss of hippocampal neurons and regulates antioxidative activity in diabetic encephalopathy rats. Phytother Res 2009; 23: 980-986
- 11 Young IC, Chuang ST, Hsu CH, Sun YJ, Liu HC, Chen YS, Lin FH. Protective effects of aucubin on osteoarthritic chondrocyte model induced by hydrogen peroxide and mechanical stimulus. BMC Complement Altern Med 2017; 17: 91
- 12 Wang J, Li Y, Huang WH, Zeng XC, Li XH, Li J, Zhou J, Xiao J, Xiao B, Ouyang DS, Hu K. The protective effect of aucubin from Eucommia ulmoides against status epilepticus by inducing autophagy and inhibiting necroptosis. Am J Chin Med 2017; 45: 557-573
- 13 Kim YM, Sim UC, Shin Y, Kim Kwon Y. Aucubin promotes neurite outgrowth in neural stem cells and axonal regeneration in sciatic nerves. Exp Neurobiol 2014; 23: 238-245
- 14 Lv PY, Feng H, Huang WH, Tian YY, Wang YQ, Qin YH, Li XH, Hu K, Zhou HH, Ouyang DS. Aucubin and its hydrolytic derivative attenuate activation of hepatic stellate cells via modulation of TGF-beta stimulation. Environ Toxicol Pharmacol 2017; 50: 234-239
- 15 Park KS. Aucubin, a naturally occurring iridoid glycoside inhibits TNF-α-induced inflammatory responses through suppression of NF-κB activation in 3T3-L1 adipocytes. Cytokine 2013; 62: 407-412
- 16 Xue HY, Niu DY, Gao GZ, Lin QY, Jin LJ, Xu YP. Aucubin modulates Bcl-2 family proteins expression and inhibits caspases cascade in H2O2-induced PC12 cells. Mol Biol Rep 2011; 38: 3561-3567
- 17 Dong S, Ma W, Hao B, Hu F, Yan L, Yan X, Wang Y, Chen Z, Wang Z. microRNA-21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up-regulating Bcl-2. Int J Clin Exp Pathol 2014; 7: 565-574
- 18 Chang Y, Guo K, Li Q, Li C, Guo Z, Li H. Multiple directional differentiation difference of neonatal rat fibroblasts from six organs. Cell Physiol Biochem 2016; 39: 157-171
- 19 Bronnum H, Eskildsen T, Andersen DC, Schneider M, Sheikh SP. IL-1beta suppresses TGF-beta-mediated myofibroblast differentiation in cardiac fibroblasts. Growth Factors 2013; 31: 81-89
- 20 Garcia R, Merino D, Gomez JM, Nistal JF, Hurle MA, Cortajarena AL, Villar AV. Extracellular heat shock protein 90 binding to TGFbeta receptor I participates in TGFbeta-mediated collagen production in myocardial fibroblasts. Cell Signal 2016; 28: 1563-1579
- 21 Fan Z, Guan J. Antifibrotic therapies to control cardiac fibrosis. Biomater Res 2016; 20: 13
- 22 Hu X, Fernandes J, Jones DP, Go YM. Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis. Toxicology 2017; 383: 50-56
- 23 Ma X, Fu Y, Xiao H, Song Y, Chen R, Shen J, An X, Shen Q, Li Z, Zhang Y. Cardiac fibrosis alleviated by exercise training is AMPK-dependent. PLoS One 2015; 10: e0129971
- 24 Sung MM, Zordoky BN, Bujak AL, Lally JS, Fung D, Young ME, Horman S, Miller EJ, Light PE, Kemp BE, Steinberg GR, Dyck JR. AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc Res 2015; 107: 235-245
- 25 He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013; 62: 1270-1281
- 26 Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, Hubbard GB, Ikeno Y, Zhang Y, Feng B, Li X, Serre T, Qi W, Van Remmen H, Miller RA, Bath KG, de Cabo R, Xu H, Neretti N, Sedivy JM. Reduced expression of MYC increases longevity and enhances healthspan. Cell 2015; 160: 477-488
- 27 Zhong JC, Zhang ZZ, Xu R, Chen LJ, Guo SJ, Xu YL, Oudit G, Jin HY, Song B, Chang Q, Gao PJ, Wang JG. Os 36-07 treatment with apelin-13 prevents pressure overload-induced aortic adventitial remodeling and fibrosis in hypertensive rats with tac. J Hypertens 2016; 34 (Suppl. 01) e403-e404
- 28 Haller ST, Yan Y, Drummond CA, Xie J, Tian J, Kennedy DJ, Shilova VY, Xie Z, Liu J, Cooper CJ, Malhotra D, Shapiro JI, Fedorova OV, Bagrov AY. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro-fibrotic signaling. J Am Heart Assoc 2016; 5: e004106
- 29 Pellman J, Zhang J, Sheikh F. Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: mechanisms and model systems. J Mol Cell Cardiol 2016; 94: 22-31
- 30 Moore-Morris T, Guimaraes-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez-Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest 2014; 124: 2921-2934
- 31 Yong KW, Li Y, Huang G, Lu TJ, Safwani WK, Pingguan-Murphy B, Xu F. Mechanoregulation of cardiac myofibroblast differentiation: implications for cardiac fibrosis and therapy. Am J Physiol Heart Circ Physiol 2015; 309: H532-H542
- 32 Creemers EE, van Rooij E. Function and therapeutic potential of noncoding RNAs in cardiac fibrosis. Circ Res 2016; 118: 108-118
- 33 Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 2014; 71: 549-574
- 34 Noppe G, Dufeys C, Buchlin P, Marquet N, Castanares-Zapatero D, Balteau M, Hermida N, Bouzin C, Esfahani H, Viollet B, Bertrand L, Balligand JL, Vanoverschelde JL, Beauloye C, Horman S. Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1. J Mol Cell Cardiol 2014; 74: 32-43
- 35 Daskalopoulos EP, Dufeys C, Bertrand L, Beauloye C, Horman S. AMPK in cardiac fibrosis and repair: actions beyond metabolic regulation. J Mol Cell Cardiol 2016; 91: 188-200
- 36 Chen KH, Hsu HH, Lee CC, Yen TH, Ko YC, Yang CW, Hung CC. The AMPK agonist AICAR inhibits TGF-β1 induced activation of kidney myofibroblasts. PLoS One 2014; 9: e106554
- 37 Tan VP, Miyamoto S. Nutrient-sensing mTORC1: integration of metabolic and autophagic signals. J Mol Cell Cardiol 2016; 95: 31-41