Asiatic acid attenuates cardiac hypertrophy by blocking transforming growth factor-β1-mediated hypertrophic signaling in vitro and in vivo

Si,Linjie; Xu,Jing; Yi,Chenlong; Xu,Xiaohan; Wang,Fang; Gu,Weijuan; Zhang,Yuqing; Wang,Xiaowei

doi:10.3892/ijmm.2014.1781

Asiatic acid attenuates cardiac hypertrophy by blocking transforming growth factor-β1-mediated hypertrophic signaling in vitro and in vivo

Authors:
- Linjie Si
- Jing Xu
- Chenlong Yi
- Xiaohan Xu
- Fang Wang
- Weijuan Gu
- Yuqing Zhang
- Xiaowei Wang
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Affiliations: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China
Published online on: May 14, 2014 https://doi.org/10.3892/ijmm.2014.1781
Pages: 499-506

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Abstract

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. Transforming growth factor-β1 (TGF-β1) signaling has been considered as a trigger causally contributing to pathological cardiac hypertrophy. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica and exhibits a variety of pharmacological effects. In this study, we investigated the anti-hypertrophic effects and mechanisms of action of AA in a TGF-β1-stimulated hypertrophic response using cultured neonatal cardiomyocytes in vitro and in a mouse model of cardiac hypertrophy induced by pressure overload in vivo. Treatment with AA markedly attenuated the TGF-β1-induced hypertrophic responses of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of atrial natriuretic peptide (ANP) mRNA expression. The protective effects of AA on hypertrophic cardiomyocytes were associated with the blocking of p38 and extracellular signal‑regulated kinase (ERK)1/2 phosphorylation and the reduction of nuclear factor-κB (NF-κB) binding activity. In vivo experiments indicated that the administration of AA prevented cardiac hypertrophy and dysfunction induced by pressure overload. It was found that AA markedly reduced the excessive production of TGF-β1 in the hypertrophic myocardium, blocked the phosphorylation of p38 and ERK1/2 and inhibited the activation of NF-κB. Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of TGF-β1‑mediated hypertrophic signaling may be the mechanism through which AA prevents cardiac hypertrophy.

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1	Frohlich ED and Susic D: Pressure overload. Heart Fail Clin. 8:21–32. 2012. View Article : Google Scholar
2	Ruwhof C and van der Laarse A: Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. 47:23–37. 2000. View Article : Google Scholar : PubMed/NCBI
3	Heineke J and Molkentin JD: Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 7:589–600. 2006. View Article : Google Scholar : PubMed/NCBI
4	Lim JY, Park SJ, Hwang HY, Park EJ, Nam JH, Kim J and Park SI: TGF-beta1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. J Mol Cell Cardiol. 39:627–636. 2005. View Article : Google Scholar : PubMed/NCBI
5	Dobaczewski M, Chen W and Frangogiannis NG: Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol. 51:600–606. 2011.
6	Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
7	Huang H, Tang QZ, Wang AB, et al: Tumor suppressor A20 protects against cardiac hypertrophy and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling. Hypertension. 56:232–239. 2010. View Article : Google Scholar : PubMed/NCBI
8	Li Y, Ha T, Gao X, et al: NF-kappaB activation is required for the development of cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol. 287:H1712–H1720. 2004. View Article : Google Scholar : PubMed/NCBI
9	Li HL, Wang AB, Huang Y, et al: Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways. Free Radic Biol Med. 38:243–257. 2005. View Article : Google Scholar : PubMed/NCBI
10	Pittella F, Dutra RC, Junior DD, Lopes MT and Barbosa NR: Antioxidant and cytotoxic activities of Centella asiatica (L) Urb. Int J Mol Sci. 10:3713–3721. 2009. View Article : Google Scholar : PubMed/NCBI
11	Yun KJ, Kim JY, Kim JB, et al: Inhibition of LPS-induced NO and PGE2 production by asiatic acid via NF-kappa B inactivation in RAW 264.7 macrophages: possible involvement of the IKK and MAPK pathways. Int Immunopharmacol. 8:431–441. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zhang X, Wu J, Dou Y, Xia B, Rong W, Rimbach G and Lou Y: Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis. Eur J Pharmacol. 679:51–59. 2012. View Article : Google Scholar : PubMed/NCBI
13	Tang LX, He RH, Yang G, et al: Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro. PLoS One. 7:e313502012. View Article : Google Scholar : PubMed/NCBI
14	Xu XH, Xu J, Xue L, Cao HL, Liu X and Chen YJ: VEGF attenuates development from cardiac hypertrophy to heart failure after aortic stenosis through mitochondrial mediated apoptosis and cardiomyocyte proliferation. J Cardiothorac Surg. 6:542011. View Article : Google Scholar
15	Feng JA, Perry G, Mori T, Hayashi T, Oparil S and Chen YF: Pressure-independent enhancement of cardiac hypertrophy in atrial natriuretic peptide-deficient mice. Clin Exp Pharmacol Physiol. 30:343–349. 2003. View Article : Google Scholar : PubMed/NCBI
16	Zhu Y, Li T, Song J, et al: The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling. Basic Res Cardiol. 106:787–799. 2011. View Article : Google Scholar : PubMed/NCBI
17	Li JM and Brooks G: Differential protein expression and subcellular distribution of TGFbeta1, beta2 and beta3 in cardiomyocytes during pressure overload-induced hypertrophy. J Mol Cell Cardiol. 29:2213–2224. 1997. View Article : Google Scholar
18	Rosenkranz S, Flesch M, Amann K, et al: Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta(1). Am J Physiol Heart Circ Physiol. 283:H1253–H1262. 2002.PubMed/NCBI
19	Wang Y: Mitogen-activated protein kinases in heart development and diseases. Circulation. 116:1413–1423. 2007. View Article : Google Scholar : PubMed/NCBI
20	LaMorte VJ, Thorburn J, Absher D, et al: Gq- and ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha 1-adrenergic stimulation. J Biol Chem. 269:13490–13496. 1994.PubMed/NCBI
21	Wang Y: Signal transduction in cardiac hypertrophy-dissecting compensatory versus pathological pathways utilizing a transgenic approach. Curr Opin Pharmacol. 1:134–140. 2001. View Article : Google Scholar : PubMed/NCBI
22	Clerk A and Sugden PH: Untangling the Web: specific signaling from PKC isoforms to MAPK cascades. Circ Res. 89:847–849. 2001.PubMed/NCBI
23	Esposito G, Prasad SV, Rapacciuolo A, Mao L, Koch WJ and Rockman HA: Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload. Circulation. 103:1453–1458. 2001. View Article : Google Scholar
24	Hall G, Hasday JD and Rogers TB: Regulating the regulator: NF-kappaB signaling in heart. J Mol Cell Cardiol. 41:580–591. 2006. View Article : Google Scholar : PubMed/NCBI
25	Gordon JW, Shaw JA and Kirshenbaum LA: Multiple Facets of NF-κB in the heart: To Be or Not to NF-κB. Circ Res. 108:1122–1132. 2011.
26	Gupta S, Young D, Maitra RK, et al: Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol. 375:637–649. 2008. View Article : Google Scholar : PubMed/NCBI