Paeonol promotes microRNA-126 expression to inhibit monocyte adhesion to ox-LDL-injured vascular endothelial cells and block the activation of the PI3K/Akt/NF-κB pathway

Yuan,Xusheng; Chen,Junjun; Dai,Min

doi:10.3892/ijmm.2016.2778

Paeonol promotes microRNA-126 expression to inhibit monocyte adhesion to ox-LDL-injured vascular endothelial cells and block the activation of the PI3K/Akt/NF-κB pathway

Authors:
- Xusheng Yuan
- Junjun Chen
- Min Dai
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Affiliations: Key Laboratory of Chinese Medicine Research and Development, Department of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230038, P.R. China, Key Laboratory of Xin'an Medicine, Department of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230038, P.R. China
Published online on: October 17, 2016 https://doi.org/10.3892/ijmm.2016.2778
Pages: 1871-1878

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Abstract

Paeonol (2'-hydroxy-4'-methoxyacetophenone) is an active component isolated from the root of Paeonia Suffruticosa Andrews. We previously found that paeonol inhibited vascular cell adhesion molecule-1 (VCAM‑1) expression, and thus may be useful for the prevention and treatment of rabbit atherosclerosis (AS); however, the underlying mechanisms are not yet well known. Recently, microRNAs (miRNAs or miRs) have been reported to play an important role in the pathogenesis of AS. In the present study, we examined the effects of paeonol on miRNA-126 (miR‑126) expression, and its ability to inhibit monocyte adhesion to oxidized low-density lipoprotein (ox-LDL)-injured vascular endothelial cells (VECs). VECs were isolated from the rat thoracic aorta and stimulated with ox-LDL (20 mg/l) in the presence of paeonol. We found that miR‑126 had a lower expression in the ox-LDL-injured VECs, and VCAM‑1 was identified as a target gene of miR‑126. Furthermore, paeonol promoted miR‑126 expression and suppressed VCAM‑1 expression at the mRNA and protein level. It also inhibited monocyte adhesion to ox-LDL-injured VECs through the promotion of miR‑126 expression. Furthermore, it was demonstrated that paeonol blocked the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor-κB (NF-κB) signaling pathway by promoting miR-126 expression. Taken together, and to the best of our knowledge, the findings of this study provide the first evidence that paeonol promotes miR‑126 expression to inhibit monocyte adhesion to ox-LDL-injured VECs and block the activation of the PI3K/Akt/NF-κB signaling pathway. Our data suggest that miR‑126 plays a crucial role in vascular inflammation and may be an important therapeutic target in the treatment of AS with the use of paeonol.

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1	Chou TC: Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia. Br J Pharmacol. 139:1146–1152. 2003. View Article : Google Scholar : PubMed/NCBI
2	Nizamutdinova IT, Jin YC, Kim JS, Yean MH, Kang SS, Kim YS, Lee JH, Seo HG, Kim HJ and Chang KC: Paeonol and paeoni-florin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats. Planta Med. 74:14–18. 2008. View Article : Google Scholar : PubMed/NCBI
3	Pan LL and Dai M: Paeonol from Paeonia suffruticosa prevents TNF-alpha-induced monocytic cell adhesion to rat aortic endothelial cells by suppression of VCAM-1 expression. Phytomedicine. 16:1027–1032. 2009. View Article : Google Scholar : PubMed/NCBI
4	Hsieh CL, Cheng CY, Tsai TH, Lin IH, Liu CH, Chiang SY, Lin JG, Lao CJ and Tang NY: Paeonol reduced cerebral infarction involving the superoxide anion and microglia activation in ischemia-reperfusion injured rats. J Ethnopharmacol. 106:208–215. 2006. View Article : Google Scholar : PubMed/NCBI
5	Su SY, Cheng CY, Tsai TH, Hsiang CY, Ho TY and Hsieh CL: Paeonol attenuates H₂O₂-induced NF-κB-associated amyloid precursor protein expression. Am J Chin Med. 38:1171–1192. 2010. View Article : Google Scholar
6	Vitaglione P, Morisco F, Caporaso N and Fogliano V: Dietary antioxidant compounds and liver health. Crit Rev Food Sci Nutr. 44:575–586. 2004. View Article : Google Scholar
7	Li H, Dai M and Jia W: Paeonol attenuates high-fat-diet-induced atherosclerosis in rabbits by anti-inflammatory activity. Planta Med. 75:7–11. 2009. View Article : Google Scholar
8	Li W, Ishihara K, Yokota T, Nakagawa T, Koyama N, Jin J, Mizuno-Horikawa Y, Wang X, Miyoshi E, Taniguchi N and Kondo A: Reduced alpha4beta1 integrin/VCAM-1 interactions lead to impaired pre-B cell repopulation in alpha 1,6-fucosyltransferase deficient mice. Glycobiology. 18:114–124. 2008. View Article : Google Scholar
9	Hwa JS, Mun L, Kim HJ, Seo HG, Lee JH, Kwak JH, Lee DU and Chang KC: Genipin selectively inhibits TNF-α-activated VCAM-1 but not ICAM-1 expression by upregulation of PPAR-γ in endothelial cells. Korean J Physiol Pharmacol. 15:157–162. 2011. View Article : Google Scholar : PubMed/NCBI
10	Tsoyi K, Kim WS, Kim YM, Kim HJ, Seo HG, Lee JH, Yun-Choi HS and Chang KC: Upregulation of PTEN by CKD712, a synthetic tetrahydroisoquinoline alkaloid, selectively inhibits lipopolysaccharide-induced VCAM-1 but not ICAM-1 expression in human endothelial cells. Atherosclerosis. 207:412–419. 2009. View Article : Google Scholar : PubMed/NCBI
11	Harris TA, Yamakuchi M, Ferlito M, Mendell JT and Lowenstein CJ: MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA. 105:1516–1521. 2008. View Article : Google Scholar : PubMed/NCBI
12	Sturgeon CM, Chicha L, Ditadi A, Zhou Q, McGrath KE, Palis J, Hammond SM, Wang S, Olson EN and Keller G: Primitive erythropoiesis is regulated by miR-126 via nonhematopoietic VCAM-1⁺ cells. Dev Cell. 23:45–57. 2012. View Article : Google Scholar : PubMed/NCBI
13	Harris TA, Yamakuchi M, Kondo M, Oettgen P and Lowenstein CJ: Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol. 30:1990–1997. 2010. View Article : Google Scholar : PubMed/NCBI
14	Nikolic I, Plate KH and Schmidt MH: EGFL7 meets miRNA-126: An angiogenesis alliance. J Angiogenes Res. 2:92010. View Article : Google Scholar : PubMed/NCBI
15	Bai Y, Bai X, Wang Z, Zhang X, Ruan C and Miao J: MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors. Exp Mol Pathol. 91:471–477. 2011. View Article : Google Scholar : PubMed/NCBI
16	Sui L, Wang J and Li BM: Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem. 15:762–776. 2008. View Article : Google Scholar : PubMed/NCBI
17	Tsubosaka Y, Murata T, Yamada K, Uemura D, Hori M and Ozaki H: Halichlorine reduces monocyte adhesion to endothelium through the suppression of nuclear factor-kappaB activation. J Pharmacol Sci. 113:208–213. 2010. View Article : Google Scholar : PubMed/NCBI
18	Ghosh S, Banerjee S and Sil PC: The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem Toxicol. 83:111–124. 2015. View Article : Google Scholar : PubMed/NCBI
19	Salvayre R, Auge N, Benoist H and Negre-Salvayre A: Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta. 1585:213–221. 2002. View Article : Google Scholar
20	Basoni C, Nobles M, Grimshaw A, Desgranges C, Davies D, Perretti M, Kramer IM and Genot E: Inhibitory control of TGF-beta1 on the activation of Rap1, CD11b, and transendothelial migration of leukocytes. FASEB J. 19:822–824. 2005.PubMed/NCBI
21	Asgeirsdóttir SA, van Solingen C, Kurniati NF, Zwiers PJ, Heeringa P, van Meurs M, Satchell SC, Saleem MA, Mathieson PW, Banas B, et al: MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation. Am J Physiol Renal Physiol. 302:F1630–F1639. 2012. View Article : Google Scholar : PubMed/NCBI
22	Rioufol G, Finet G, Ginon I, André-Fouët X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF and Tabib A: Multiple atherosclerotic plaque rupture in acute coronary syndrome: A three-vessel intravascular ultrasound study. Circulation. 106:804–808. 2002. View Article : Google Scholar : PubMed/NCBI
23	Peng N, Meng N, Wang S, Zhao F, Zhao J, Su L, Zhang S, Zhang Y, Zhao B and Miao J: An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E^−/− mice. Sci Rep. 4:55192014.
24	Fuentes E, Palomo I and Alarcón M: Platelet miRNAs and cardiovascular diseases. Life Sci. 133:29–44. 2015. View Article : Google Scholar : PubMed/NCBI
25	Condorelli G, Latronico MV and Cavarretta E: microRNAs in cardiovascular diseases: Current knowledge and the road ahead. J Am Coll Cardiol. 63:2177–2187. 2014. View Article : Google Scholar : PubMed/NCBI
26	Angel-Morales G, Noratto G and Mertens-Talcott SU: Standardized curcuminoid extract (Curcuma longa L.) decreases gene expression related to inflammation and interacts with associated microRNAs in human umbilical vein endothelial cells (HUVEC). Food Funct. 3:1286–1293. 2012. View Article : Google Scholar : PubMed/NCBI
27	Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R and Olson EN: The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 15:261–271. 2008. View Article : Google Scholar : PubMed/NCBI
28	Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW and Milstone DS: A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 107:1255–1262. 2001. View Article : Google Scholar : PubMed/NCBI
29	Libby P: Inflammation in atherosclerosis. Nature. 420:868–874. 2002. View Article : Google Scholar : PubMed/NCBI
30	Croft D, McIntyre P, Wibulswas A and Kramer I: Sustained elevated levels of VCAM-1 in cultured fibroblast-like synoviocytes can be achieved by TNF-alpha in combination with either IL-4 or IL-13 through increased mRNA stability. Am J Pathol. 154:1149–1158. 1999. View Article : Google Scholar : PubMed/NCBI
31	Hayden MS and Ghosh S: Signaling to NF-kappaB. Genes Dev. 18:2195–2224. 2004. View Article : Google Scholar : PubMed/NCBI
32	Albelda SM, Smith CW and Ward PA: Adhesion molecules and inflammatory injury. FASEB J. 8:504–512. 1994.PubMed/NCBI
33	Lockyer JM, Colladay JS, Alperin-Lea WL, Hammond T and Buda AJ: Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circ Res. 82:314–320. 1998. View Article : Google Scholar : PubMed/NCBI
34	Yang M, Huang J, Pan HZ and Jin J: Triptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/NF-κB pathways in human multiple myeloma cells. Int J Mol Med. 22:489–496. 2008.PubMed/NCBI
35	Wang XC, Du LQ, Tian LL, Wu HL, Jiang XY, Zhang H, Li DG, Wang YY, Wu HY, She Y, et al: Expression and function of miRNA in postoperative radiotherapy sensitive and resistant patients of non-small cell lung cancer. Lung Cancer. 72:92–99. 2011. View Article : Google Scholar
36	Guo C, Sah JF, Beard L, Willson JK, Markowitz SD and Guda K: The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer. 47:939–946. 2008. View Article : Google Scholar : PubMed/NCBI
37	Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY and Srivastava D: miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 15:272–284. 2008. View Article : Google Scholar : PubMed/NCBI
38	Sessa R, Seano G, di Blasio L, Gagliardi PA, Isella C, Medico E, Cotelli F, Bussolino F and Primo L: The miR-126 regulates angiopoietin-1 signaling and vessel maturation by targeting p85β. Biochim Biophys Acta. 1823:1925–1935. 2012. View Article : Google Scholar : PubMed/NCBI