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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Tanshinone IIA Promotes Macrophage Cholesterol Efflux and Attenuates Atherosclerosis of apoE-/- Mice by Omentin-1/ABCA1 Pathway

Author(s): Yu-lin Tan, Han-xiao Ou, Min Zhang, Duo Gong, Zhen-wang Zhao, Ling-yan Chen, Xiao-dan Xia, Zhong-cheng Mo* and Chao-ke Tang*

Volume 20, Issue 5, 2019

Page: [422 - 432] Pages: 11

DOI: 10.2174/1389201020666190404125213

Price: $65

Abstract

Background: Tanshinone IIA (Tan IIA) and Omentin-1 have a protective role in the cardiovascular system. However, if and how Tan IIA and Omentin-1 regulate cholesterol metabolism in macrophages has not been fully elucidated.

Objective: To investigate the possible mechanisms of Tan IIA and Omentin-1 on preventing macrophage cholesterol accumulation and atherosclerosis development.

Methods: The effect of Tan IIA on the protein and mRNA levels of Omentin-1 and ATP-binding cassette transporter A1 (ABCA1) in macrophages was examined by Western blot and qRT-PCR assay, respectively. Cholesterol efflux was assessed by liquid scintillation counting (LSC). Cellular lipid droplet was measured by Oil Red O staining, and intracellular lipid content was detected by high performance liquid chromatography (HPLC). In addition, the serum lipid profile of apoE−/− mice was measured by enzymatic method. The size of atherosclerotic lesion areas and content of lipids and collagen in the aortic of apoE−/− mice were examined by Sudan IV, Oil-red O, and Masson staining, respectively.

Results: Tan IIA up-regulated expression of Omentin-1 and ABCA1 in THP-1 macrophages, promoting ABCA1-mediated cholesterol efflux and consequently decreasing cellular lipid content. Consistently, Tan IIA increased reverse cholesterol transport in apoE−/− mice. Plasma levels of high-density lipoprotein cholesterol (HDL-C), ABCA1 expression and atherosclerotic plaque collagen content were increased while plasma levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic plaque sizes were reduced in Tan IIA-treated apoE−/− mice. These beneficial effects were, however, essentially blocked by knockdown of Omentin-1.

Conclusion: Our results revealed that Tan IIA promotes cholesterol efflux and ameliorates lipid accumulation in macrophages most likely via the Omentin-1/ABCA1 pathway, reducing the development of aortic atherosclerosis.

Keywords: Tan IIA, Omentin-1, ABCA1, cholesterol efflux, reverse cholesterol transport, plaque vulnerability.

Graphical Abstract

[1]
Liu, Z.; Wang, J.; Huang, E.; Gao, S.; Li, H.; Lu, J.; Tian, K.; Little, P.J.; Shen, X.; Xu, S.; Liu, P. Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1. J. Lipid Res., 2014, 55(2), 201-213.
[2]
Yu, X.H.; Zhang, D.W.; Zheng, X.L.; Tang, C.K. Cholesterol transport system: An integrated cholesterol transport model involved in atherosclerosis. Prog. Lipid Res., 2019, 73, 65-91.
[3]
Moore, K.J.; Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell, 2011, 145(3), 341-355.
[4]
Reiss, A.B.; Vernice, N.A.; Siegart, N.M.; DeLeon, J.; Kasselman, L.J. Exosomes in cholesterol metabolism and atherosclerosis. Cardiovasc. Hematol. Disord. Drug Targets, 2018, 17(3), 185-194.
[5]
Zhao, Z.W.; Zhang, M.; Chen, L.Y.; Gong, D.; Xia, X.D.; Yu, X.H.; Wang, S.Q.; Ou, X.; Dai, X.Y.; Zheng, X.L.; Zhang, D.W.; Tang, C.K. Heat shock protein 70 accelerates atherosclerosis by downregulating the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2018, 1863(8), 806-822.
[6]
Hu, Y.W.; Wang, Q.; Ma, X.; Li, X.X.; Liu, X.H.; Xiao, J.; Liao, D.F.; Xiang, J.; Tang, C.K. TGF-beta1 up-regulates expression of ABCA1, ABCG1 and SR-BI through liver X receptor alpha signaling pathway in THP-1 macrophage-derived foam cells. J. Atheroscler. Thromb., 2010, 17(5), 493-502.
[7]
Tang, F.; Wu, X.; Wang, T.; Wang, P.; Li, R.; Zhang, H.; Gao, J.; Chen, S.; Bao, L.; Huang, H.; Liu, P. Tanshinone II A attenuates atherosclerotic calcification in rat model by inhibition of oxidative stress. Vascul. Pharmacol., 2007, 46(6), 427-438.
[8]
Xu, S.; Little, P.J.; Lan, T.; Huang, Y.; Le, K.; Wu, X.; Shen, X.; Huang, H.; Cai, Y.; Tang, F.; Wang, H.; Liu, P. Tanshinone II-A attenuates and stabilizes atherosclerotic plaques in apolipoprotein-E knockout mice fed a high cholesterol diet. Arch. Biochem. Biophys., 2011, 515(1-2), 72-79.
[9]
Li, X.; Du, J.R.; Yu, Y.; Bai, B.; Zheng, X.Y. Tanshinone IIA inhibits smooth muscle proliferation and intimal hyperplasia in the rat carotid balloon-injured model through inhibition of MAPK signaling pathway. J. Ethnopharmacol., 2010, 129(2), 273-279.
[10]
Zhu, J.; Xu, Y.; Ren, G.; Hu, X.; Wang, C.; Yang, Z.; Li, Z.; Mao, W.; Lu, D.; Tanshinone, I.I.A. Sodium sulfonate regulates antioxidant system, inflammation, and endothelial dysfunction in atherosclerosis by downregulation of CLIC1. Eur. J. Pharmacol., 2017, 815, 427-436.
[11]
Gao, S.; Liu, Z.; Li, H.; Little, P.J.; Liu, P.; Xu, S. Cardiovascular actions and therapeutic potential of tanshinone IIA. Atherosclerosis, 2012, 220(1), 3-10.
[12]
Pan, H.Y.; Guo, L.; Li, Q. Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes. Diabetes Res. Clin. Pract., 2010, 88(1), 29-33.
[13]
Kazama, K.; Usui, T.; Okada, M.; Hara, Y.; Yamawaki, H. Omentin plays an anti-inflammatory role through inhibition of TNF-alpha-induced superoxide production in vascular smooth muscle cells. Eur. J. Pharmacol., 2012, 686(1-3), 116-123.
[14]
Yamawaki, H.; Tsubaki, N.; Mukohda, M.; Okada, M.; Hara, Y. Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. Biochem. Biophys. Res. Commun., 2010, 393(4), 668-672.
[15]
Watanabe, K.; Watanabe, R.; Konii, H.; Shirai, R.; Sato, K.; Matsuyama, T.A.; Ishibashi-Ueda, H.; Koba, S.; Kobayashi, Y.; Hirano, T.; Watanabe, T. Counteractive effects of omentin-1 against atherogenesisdagger. Cardiovasc. Res., 2016, 110(1), 118-128.
[16]
Zhang, Y.; Zanotti, I.; Reilly, M.P.; Glick, J.M.; Rothblat, G.H.; Rader, D.J. Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo. Circulation, 2003, 108(6), 661-663.
[17]
Lv, Y.C.; Tang, Y.Y.; Peng, J.; Zhao, G.J.; Yang, J.; Yao, F.; Ouyang, X.P.; He, P.P.; Xie, W.; Tan, Y.L.; Zhang, M.; Liu, D.; Tang, D.P.; Cayabyab, F.S.; Zheng, X.L.; Zhang, D.W.; Tian, G.P.; Tang, C.K. MicroRNA-19b promotes macrophage cholesterol accumulation and aortic atherosclerosis by targeting ATP-binding cassette transporter A1. Atherosclerosis, 2014, 236(1), 215-226.
[18]
Tangirala, R.K.; Rubin, E.M.; Palinski, W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J. Lipid Res., 1995, 36(11), 2320-2328.
[19]
Heinecke, J.W. Small HDL promotes cholesterol efflux by the ABCA1 pathway in macrophages: Implications for therapies targeted to HDL. Circ. Res., 2015, 116(7), 1101-1103.
[20]
Hafiane, A.; Genest, J. ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis. Atherosclerosis, 2017, 257, 90-99.
[21]
Yoo, H.J.; Hwang, S.Y.; Hong, H.C.; Choi, H.Y.; Yang, S.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Choi, K.M.; Choi, D.S.; Baik, S.H. Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes. Cardiovasc. Diabetol., 2011, 10, 103.
[22]
Liu, R.; Wang, X.; Bu, P. Omentin-1 is associated with carotid atherosclerosis in patients with metabolic syndrome. Diabetes Res. Clin. Pract., 2011, 93(1), 21-25.
[23]
Xu, T.; Zuo, P.; Cao, L.; Gao, Z.; Ke, K. Omentin-1 is associated with carotid plaque instability among ischemic stroke patients. J. Atheroscler. Thromb., 2018, 25(6), 505-511.
[24]
Lu, X. The role of exosomes and exosome-derived microRNAs in atherosclerosis. Curr. Pharm. Des., 2017, 23(40), 6182-6193.
[25]
Jiang, J.; Mo, Z.C.; Yin, K.; Zhao, G.J.; Lv, Y.C.; Ouyang, X.P.; Jiang, Z.S.; Fu, Y.; Tang, C.K. Epigallocatechin-3-gallate prevents TNF-alpha-induced NF-kappaB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells. Int. J. Mol. Med., 2012, 29(5), 946-956.
[26]
Chen, S.G.; Xiao, J.; Liu, X.H.; Liu, M.M.; Mo, Z.C.; Yin, K.; Zhao, G.J.; Jiang, J.; Cui, L.B.; Tan, C.Z.; Yin, W.D.; Tang, C.K. Ibrolipim increases ABCA1/G1 expression by the LXRalpha signaling pathway in THP-1 macrophage-derived foam cells. Acta Pharmacol. Sin., 2010, 31(10), 1343-1349.
[27]
Chen, T.H.; Hsu, Y.T.; Chen, C.H.; Kao, S.H.; Lee, H.M. Tanshinone IIA from Salvia miltiorrhiza induces heme oxygenase-1 expression and inhibits lipopolysaccharide-induced nitric oxide expression in RAW 264.7 cells. Mitochondrion, 2007, 7(1-2), 101-105.
[28]
Gao, S.; Liu, Z.; Li, H.; Little, P.J.; Liu, P.; Xu, S. Cardiovascular actions and therapeutic potential of tanshinone IIA. Atherosclerosis, 2012, 220(1), 3-10.
[29]
Wang, X.; Morris-Natschke, S.L.; Lee, K.H. New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med. Res. Rev., 2007, 27(1), 133-148.
[30]
Shang, Q.; Wang, H.; Li, S.; Xu, H. The effect of sodium tanshinone iia sulfate and simvastatin on elevated serum levels of inflammatory markers in patients with coronary heart disease: a study protocol for a randomized controlled trial. Evid. Based Complement. Alternat. Med., 2013, 2013756519
[31]
Lesna, J.; Ticha, A.; Hyspler, R.; Musil, F.; Blaha, V.; Sobotka, L.; Zadak, Z.; Smahelova, A. Omentin-1 plasma levels and cholesterol metabolism in obese patients with diabetes mellitus type 1: Impact of weight reduction. Nutr. Diabetes, 2015, 5e183
[32]
Maruyama, S.; Shibata, R.; Kikuchi, R.; Izumiya, Y.; Rokutanda, T.; Araki, S.; Kataoka, Y.; Ohashi, K.; Daida, H.; Kihara, S.; Ogawa, H.; Murohara, T.; Ouchi, N. Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism. J. Biol. Chem., 2012, 287(1), 408-417.
[33]
Uemura, Y.; Shibata, R.; Kanemura, N.; Ohashi, K.; Kambara, T.; Hiramatsu-Ito, M.; Enomoto, T.; Yuasa, D.; Joki, Y.; Matsuo, K.; Ito, M.; Hayakawa, S.; Ogawa, H.; Murohara, T.; Ouchi, N. Adipose-derived protein omentin prevents neointimal formation after arterial injury. FASEB J., 2015, 29(1), 141-151.
[34]
Kataoka, Y.; Shibata, R.; Ohashi, K.; Kambara, T.; Enomoto, T.; Uemura, Y.; Ogura, Y.; Yuasa, D.; Matsuo, K.; Nagata, T.; Oba, T.; Yasukawa, H.; Numaguchi, Y.; Sone, T.; Murohara, T.; Ouchi, N. Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. J. Am. Coll. Cardiol., 2014, 63(24), 2722-2733.
[35]
Kazama, K.; Okada, M.; Yamawaki, H. A novel adipocytokine, omentin, inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell migration through antioxidative mechanism. Am. J. Physiol. Heart Circ. Physiol., 2014, 306(12), H1714-H1719.
[36]
Duan, X.Y.; Xie, P.L.; Ma, Y.L.; Tang, S.Y. Omentin inhibits osteoblastic differentiation of calcifying vascular smooth muscle cells through the PI3K/Akt pathway. Amino Acids, 2011, 41(5), 1223-1231.
[37]
Du, Y.; Ji, Q.; Cai, L.; Huang, F.; Lai, Y.; Liu, Y.; Yu, J.; Han, B.; Zhu, E.; Zhang, J.; Zhou, Y.; Wang, Z.; Zhao, Y. Association between omentin-1 expression in human epicardial adipose tissue and coronary atherosclerosis. Cardiovasc. Diabetol., 2016, 15, 90.
[38]
Seimon, T.A.; Nadolski, M.J.; Liao, X.; Magallon, J.; Nguyen, M.; Feric, N.T.; Koschinsky, M.L.; Harkewicz, R.; Witztum, J.L.; Tsimikas, S.; Golenbock, D.; Moore, K.J.; Tabas, I. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab., 2010, 12(5), 467-482.
[39]
Sacks, F.M.; Jensen, M.K. From high-density lipoprotein cholesterol to measurements of function: Prospects for the development of tests for high-density lipoprotein functionality in cardiovascular disease. Arterioscler. Thromb. Vasc. Biol., 2018, 38(3), 487-499.
[40]
Zou, T.B.; Zhu, S.S.; Luo, F.; Li, W.Q.; Sun, X.R.; Wu, H.F. effects of astaxanthin on reverse cholesterol transport and atherosclerosis in mice. BioMed Res. Int., 2017, 20174625932
[41]
Eilenberg, W.; Stojkovic, S.; Kaider, A.; Kozakowski, N.; Domenig, C.M.; Burghuber, C.; Nanobachvili, J.; Huber, K.; Klinger, M.; Neumayer, C.; Huk, I.; Wojta, J.; Demyanets, S. NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis. Clin. Chem. Lab. Med., 2017, 56(1), 147-156.
[42]
Xu, T.; Zuo, P.; Cao, L.; Gao, Z.; Ke, K. Omentin-1 is associated with carotid plaque instability among ischemic stroke patients. J. Atheroscler. Thromb., 2017, 25(6), 505-511.

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