Effect of asiaticoside on endothelial cells in hypoxia‑induced pulmonary hypertension

Wang,Xiaobing; Cai,Xueli; Wang,Wu; Jin,Yi; Chen,Mayun; Huang,Xiaoying; Zhu,Xiaochun; Wang,Liangxing

doi:10.3892/mmr.2017.8254

Effect of asiaticoside on endothelial cells in hypoxia‑induced pulmonary hypertension

Authors:
- Xiaobing Wang
- Xueli Cai
- Wu Wang
- Yi Jin
- Mayun Chen
- Xiaoying Huang
- Xiaochun Zhu
- Liangxing Wang
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Affiliations: Department of Rheumalogy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China, Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China, Key Laboratory of Heart and Lung, Respiratory Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
Published online on: December 12, 2017 https://doi.org/10.3892/mmr.2017.8254
Pages: 2893-2900
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pulmonary hypertension (PH) is a chronic progressive disease with limited treatment options. The exact etiology and pathogenesis of PH remain to be elucidated, however there is novel evidence that implicates abnormal endothelial cells (ECs) apoptosis and dysfunction of ECs to be involved in the initiation of PH. Asiaticoside (AS) is a saponin monomer extracted from a medicinal plant called Centella asiatica, which had a preventing effect of hypoxia‑induced pulmonary hypertension (hypoxic PH) by blocking transforming growth factor‑β1/SMAD family member 2/3 signaling in our previous study. The present study demonstrated that AS can prevent the development of hypoxic PH and reverse the established hypoxic PH. AS may activate the nitric oxide (NO)‑mediated signals by enhancing the phosphorylation of serine/threonine‑specific protein kinase/eNOS, thus promoting NO production, and prevent ECs from hypoxia‑induced apoptosis. All these findings imply that AS may be a potential therapeutic option for hypoxic PH patients due to its effect on the vitality and function of endothelial cells.

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1	Rubin LJ: Primary pulmonary hypertension. N Engl J Med. 336:111–117. 1997. View Article : Google Scholar : PubMed/NCBI
2	Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF and Rabinovitch M: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 43 12 Suppl S:13S–24S. 2004. View Article : Google Scholar : PubMed/NCBI
3	Shimoda LA, Sham JS and Sylvester JT: Altered pulmonary vasoreactivity in the chronically hypoxic lung. Physiol Res. 49:549–560. 2000.PubMed/NCBI
4	Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, et al: Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA. 104:pp. 1342–1347. 2007; View Article : Google Scholar : PubMed/NCBI
5	Campbell AI, Zhao Y, Sandhu R and Stewart DJ: Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation. 104:2242–2248. 2001. View Article : Google Scholar : PubMed/NCBI
6	Zhao YD, Campbell AI, Robb M, Ng D and Stewart DJ: Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res. 92:984–991. 2003. View Article : Google Scholar : PubMed/NCBI
7	Le Cras TD and McMurtry IF: Nitric oxide production in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol. 280:L575–L582. 2001. View Article : Google Scholar : PubMed/NCBI
8	Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A and Sessa WC: Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 399:597–601. 1999. View Article : Google Scholar : PubMed/NCBI
9	Ou J, Fontana JT, Ou Z, Jones DW, Ackerman AW, Oldham KT, Yu J, Sessa WC and Pritchard KA Jr: Heat shock protein 90 and tyrosine kinase regulate eNOS NO* generation but not NO* bioactivity. Am J Physiol Heart Circ Physiol. 286:H561–H569. 2004. View Article : Google Scholar : PubMed/NCBI
10	Giaid A and Saleh D: Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 333:214–221. 1995. View Article : Google Scholar : PubMed/NCBI
11	Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, Aigner C, Fink L, Muyal JP, Weissmann N, et al: Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. 19:1175–1177. 2005.PubMed/NCBI
12	Guo JS, Cheng CL and Koo MW: Inhibitory effects of Centella asiatica water extract and asiaticoside on inducible nitric oxide synthase during gastric ulcer healing in rats. Planta Med. 70:1150–1154. 2004. View Article : Google Scholar : PubMed/NCBI
13	Yun KJ, Kim JY, Kim JB, Lee KW, Jeong SY, Park HJ, Jung HJ, Cho YW, Yun K and Lee KT: 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
14	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
15	Chen S, Yin ZJ, Jiang C, Ma ZQ, Fu Q, Qu R and Ma SP: Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism. Pharmacol Biochem Behav. 122:7–15. 2014. View Article : Google Scholar : PubMed/NCBI
16	Wang XB, Wang W, Zhu XC, Ye WJ, Cai H, Wu PL, Huang XY and Wang LX: The potential of asiaticoside for TGF-β1/Smad signaling inhibition in prevention and progression of hypoxia-induced pulmonary hypertension. Life Sci. 137:56–64. 2015. View Article : Google Scholar : PubMed/NCBI
17	Muramatsu M, Oka M, Morio Y, Soma S, Takahashi H and Fukuchi Y: Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs. Am J Physiol. 276:L358–L364. 1999.PubMed/NCBI
18	Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R and Archer SL: Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation. 105:244–250. 2002. View Article : Google Scholar : PubMed/NCBI
19	Zheng Y, Li M, Zhang Y, Shi X, Li L and Jin M: The effects and mechanisms of mycophenolate mofetil on pulmonary arterial hypertension in rats. Rheumatol Int. 30:341–348. 2010. View Article : Google Scholar : PubMed/NCBI
20	Mukhopadhyay S, Xu F and Sehgal PB: Aberrant cytoplasmic sequestration of eNOS in endothelial cells after monocrotaline, hypoxia and senescence: Live-cell caveolar and cytoplasmic NO imaging. Am J Physiol Heart Circ Physiol. 292:H1373–H1389. 2007. View Article : Google Scholar : PubMed/NCBI
21	Wilkins MR: Pulmonary hypertension: The science behind the disease spectrum. Eur Respir Rev. 21:19–26. 2012. View Article : Google Scholar : PubMed/NCBI
22	Coggins MP and Bloch KD: Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol. 27:1877–1885. 2007. View Article : Google Scholar : PubMed/NCBI
23	Song G, Ouyang G and Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 9:59–71. 2005. View Article : Google Scholar : PubMed/NCBI
24	Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS and Dzau VJ: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 9:1195–1201. 2003. View Article : Google Scholar : PubMed/NCBI
25	Martorell L, Gentile M, Rius J, Rodríguez C, Crespo J, Badimon L and Martínez-González J: The hypoxia-inducible factor 1/NOR-1 axis regulates the survival response of endothelial cells to hypoxia. Mol Cell Biol. 29:5828–5842. 2009. View Article : Google Scholar : PubMed/NCBI
26	Pullamsetti SS, Savai R, Janssen W, Dahal BK, Seeger W, Grimminger F, Ghofrani HA, Weissmann N and Schermuly RT: Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin Microbiol Infect. 17:7–14. 2011. View Article : Google Scholar : PubMed/NCBI