Asiatic acid inhibits left ventricular remodeling and improves cardiac function in a rat model of myocardial infarction

Huo,Lianying; Shi,Wenbing; Chong,Ling; Wang,Jinlong; Zhang,Kai; Li,Yufeng

doi:10.3892/etm.2015.2871

Asiatic acid inhibits left ventricular remodeling and improves cardiac function in a rat model of myocardial infarction

Authors:
- Lianying Huo
- Wenbing Shi
- Ling Chong
- Jinlong Wang
- Kai Zhang
- Yufeng Li
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Affiliations: Department of Cardiology, Shanxian Dongda Hospital, Shanxian, Shandong 274300, P.R. China, Department of Cardiology, Heze Shili Hospital, Heze, Shandong 274000, P.R. China, Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China
Published online on: November 17, 2015 https://doi.org/10.3892/etm.2015.2871
Pages: 57-64
Copyright: © Huo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Left ventricular remodeling results in cardiac dysfunction and accounts for the majority of the morbidity and mortality following myocardial infarction (MI). The aim of the present study was to investigate the effect of asiatic acid (AA) on cardiac function and left ventricular remodeling in a rat model of MI and explore the underlying mechanisms. Rats were subjected to coronary artery ligation to model MI and orally treated with AA. After 4 weeks, cardiac function was assessed by echocardiography. Cardiomyocyte cross‑sectional area was recorded, and the expression levels of a number of inflammatory cytokines were detected using ELISA. The degree of interstitial fibrosis was determined by evaluating the mRNA expression levels of collagen II and III. Western blot analysis was performed to detect the expression levels of total and phosphorylated p38 MAPK and ERK1/2, to investigate whether they are involved in the mechanism underlying the effect of AA on the heart. Rats subjected to MI displayed significantly impaired cardiac function compared with those subjected to a sham procedure, while this change was reversed by treatment with AA. Furthermore, AA markedly inhibited cardiac hypertrophy, reduced the mRNA expression levels of inflammatory cytokines and decreased interstitial fibrosis in the infarct border zone of MI model rats compared with those in vehicle‑treated MI model rats. Furthermore, the phosphorylation of p38 MAPK and ERK1/2 was blocked by AA in the MI rats but not in the sham rats. In summary, AA treatment preserved cardiac function and inhibited left ventricular remodeling, potentially by blocking the phosphorylation of p38 MAPK and ERK1/2 in the infarct border zone of the ischemic myocardium, indicating that AA may be a novel candidate for development as a therapy for MI.

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1	Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, et al: Heart disease and stroke statistics-2012 update: A report from the American Heart Association. Circulation. 125:e2–e220. 2012. View Article : Google Scholar : PubMed/NCBI
2	Opie LH, Commerford PJ, Gersh BJ and Pfeffer MA: Controversies in ventricular remodelling. Lancet. 367:356–367. 2006. View Article : Google Scholar : PubMed/NCBI
3	Biomarkers, genomics, telemetry, computational biology and zebrafish: Will one of these solve the problems of post-myocardial infarction heart failure? Eur Heart J. 35:57–58. 2014.PubMed/NCBI
4	Khan R and Sheppard R: Fibrosis in heart disease: Understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology. 118:10–24. 2006. View Article : Google Scholar : PubMed/NCBI
5	Mann DL: Mechanisms and models in heart failure: A combinatorial approach. Circulation. 100:999–1008. 1999. View Article : Google Scholar : PubMed/NCBI
6	Fosshaug LE, Berge RK, Beitnes JO, Berge K, Vik H, Aukrust P, Gullestad L, Vinge LE and Øie E: Krill oil attenuates left ventricular dilatation after myocardial infarction in rats. Lipids Health Dis. 10:2452011. View Article : Google Scholar : PubMed/NCBI
7	Yang F, Yang XP, Liu YH, Xu J, Cingolani O, Rhaleb NE and Carretero OA: Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction. Hypertension. 43:229–236. 2004. View Article : Google Scholar : PubMed/NCBI
8	Jugdutt BI: Aging and remodeling during healing of the wounded heart: Current therapies and novel drug targets. Curr Drug Targets. 9:325–344. 2008. View Article : Google Scholar : PubMed/NCBI
9	Nicoletti A, Heudes D, Mandet C, Hinglais N, Bariety J and Michel JB: Inflammatory cells and myocardial fibrosis: Spatial and temporal distribution in renovascular hypertensive rats. Cardiovasc Res. 32:1096–1107. 1996. View Article : Google Scholar : PubMed/NCBI
10	Bujak M and Frangogiannis NG: The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 74:184–195. 2007. View Article : Google Scholar : PubMed/NCBI
11	Zhang H, Wu J, Dong H, Khan SA, Chu ML and Tsuda T: Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling. Clin Sci (Lond). 126:275–288. 2014. View Article : Google Scholar : PubMed/NCBI
12	Muslin AJ: MAPK signalling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets. Clin Sci (Lond). 115:203–218. 2008. View Article : Google Scholar : PubMed/NCBI
13	Yeh CC, Li H, Malhotra D, Turcato S, Nicholas S, Tu R, Zhu BQ, Cha J, Swigart PM, Myagmar BE, et al: Distinctive ERK and p38 signaling in remote and infarcted myocardium during post-MI remodeling in the mouse. J Cell Biochem. 109:1185–1191. 2010.PubMed/NCBI
14	Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, et al: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 456:980–984. 2008. View Article : Google Scholar : PubMed/NCBI
15	Krishnamurthy RG, Senut MC, Zemke D, Min J, Frenkel MB, Greenberg EJ, Yu SW, Ahn N, Goudreau J, Kassab M, et al: Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia. J Neurosci Res. 87:2541–2550. 2009. View Article : Google Scholar : PubMed/NCBI
16	Huang SS, Chiu CS, Chen HJ, Hou WC, Sheu MJ, Lin YC, Shie PH and Huang GJ: Antinociceptive activities and the mechanisms of anti-inflammation of asiatic acid in mice. Evid Based Complement Alternat Med. 2011:8958572011. View Article : Google Scholar : PubMed/NCBI
17	Ramachandran V, Saravanan R and Senthilraja P: Antidiabetic and antihyperlipidemic activity of asiatic acid in diabetic rats, role of HMG CoA: In vivo and in silico approaches. Phytomedicine. 21:225–232. 2014. View Article : Google Scholar : PubMed/NCBI
18	Bian D, Zhang J, Wu X, Dou Y, Yang Y, Tan Q, Xia Y, Gong Z and Dai Y: Asiatic acid isolated from Centella asiatica inhibits TGF-β1-induced collagen expression in human keloid fibroblasts via PPAR-γ activation. Int J Biol Sci. 9:1032–1042. 2013. View Article : Google Scholar : PubMed/NCBI
19	Dong MS, Jung SH, Kim HJ, Kim JR, Zhao LX, Lee ES, Lee EJ, Yi JB, Lee N, Cho YB, et al: Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid derivatives in rat hepatic stellate cell-line, HSC-T6. Arch Pharm Res. 27:512–517. 2004. View Article : Google Scholar : PubMed/NCBI
20	Tang LX, He RH, Yang G, Tan JJ, Zhou L, Meng XM, Huang XR and Lan HY: 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
21	Si L, Xu J, Yi C, Xu X, Wang F, Gu W, Zhang Y and Wang X: Asiatic acid attenuates cardiac hypertrophy by blocking transforming growth factor-β1-mediated hypertrophic signaling in vitro and in vivo. Int J Mol Med. 34:499–506. 2014.PubMed/NCBI
22	Chan CY, Mong MC, Liu WH, Huang CY and Yin MC: Three pentacyclic triterpenes protect H9c2 cardiomyoblast cells against high-glucose-induced injury. Free Radic Res. 48:402–411. 2014. View Article : Google Scholar : PubMed/NCBI
23	Orenstein TL, Parker TG, Butany JW, Goodman JM, Dawood F, Wen WH, Wee L, Martino T, McLaughlin PR and Liu PP: Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression. J Clin Invest. 96:858–866. 1995. View Article : Google Scholar : PubMed/NCBI
24	Bunbupha S, Pakdeechote P, Kukongviriyapan U, Prachaney P and Kukongviriyapan V: Asiatic acid reduces blood pressure by enhancing nitric oxide bioavailability with modulation of eNOS and p47phox expression in L-NAME-induced hypertensive rats. Phytother Res. 28:1506–1512. 2014. View Article : Google Scholar : PubMed/NCBI
25	Lee KY, Bae ON, Serfozo K, Hejabian S, Moussa A, Reeves M, Rumbeiha W, Fitzgerald SD, Stein G, Baek SH, et al: Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia. Stroke. 43:1632–1638. 2012. View Article : Google Scholar : PubMed/NCBI
26	Araki S, Izumiya Y, Hanatani S, Rokutanda T, Usuku H, Akasaki Y, Takeo T, Nakagata N, Walsh K and Ogawa H: Akt1-mediated skeletal muscle growth attenuates cardiac dysfunction and remodeling after experimental myocardial infarction. Circ Heart Fail. 5:116–125. 2012. View Article : Google Scholar : PubMed/NCBI
27	Vahtola E, Louhelainen M, Merasto S, Martonen E, Penttinen S, Aahos I, Kytö V, Virtanen I and Mervaala E: Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat. J Hypertens. 26:334–344. 2008. View Article : Google Scholar : PubMed/NCBI
28	Pan Z, Zhao W, Zhang X, Wang B, Wang J, Sun X, Liu X, Feng S, Yang B and Lu Y: Scutellarin alleviates interstitial fibrosis and cardiac dysfunction of infarct rats by inhibiting TGFβ1 expression and activation of p38-MAPK and ERK1/2. Br J Pharmacol. 162:688–700. 2011. View Article : Google Scholar : PubMed/NCBI
29	Zhu D, Wang H, Zhang J, Zhang X, Xin C, Zhang F, Lee Y, Zhang L, Lian K, Yan W, et al: Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. J Mol Cell Cardiol. 87:138–147. 2015. View Article : Google Scholar : PubMed/NCBI
30	Chen P, Pang S, Yang N, Meng H, Liu J, Zhou N, Zhang M, Xu Z, Gao W, Chen B, et al: Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction. PLoS One. 8:e794182013. View Article : Google Scholar : PubMed/NCBI
31	Okada H, Takemura G, Kosai K, Li Y, Takahashi T, Esaki M, Yuge K, Miyata S, Maruyama R, Mikami A, et al: Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation. 111:2430–2437. 2005. View Article : Google Scholar : PubMed/NCBI
32	Kurrelmeyer K, Kalra D, Bozkurt B, Wang F, Dibbs Z, Seta Y, Baumgarten G, Engle D, Sivasubramanian N and Mann DL: Cardiac remodeling as a consequence and cause of progressive heart failure. Clin Cardiol. 21:I14–I19. 1998. View Article : Google Scholar : PubMed/NCBI
33	Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP and Schaper J: Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation. 107:984–991. 2003. View Article : Google Scholar : PubMed/NCBI
34	White HD and Braunwald E: Applying the open artery theory: Use of predictive survival markers. Eur Heart J. 19:1132–1139. 1998. View Article : Google Scholar : PubMed/NCBI
35	Vanhoutte D, Schellings M, Pinto Y and Heymans S: Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window. Cardiovasc Res. 69:604–613. 2006. View Article : Google Scholar : PubMed/NCBI
36	Ren J, Zhang S, Kovacs A, Wang Y and Muslin AJ: Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J Mol Cell Cardiol. 38:617–623. 2005. View Article : Google Scholar : PubMed/NCBI