Adiponectin improves NF-κB-mediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice
Tóm tắt
Atherosclerosis is a common pathological basis of cardiovascular disease. Adiponectin (APN) has been shown to have an anti-atherosclerosis effect, and the underlying mechanisms, however, are largely unknown. Nuclear factor κB (NF-κB) has also been regarded as a proatherogenic factor, mainly because of its regulation of a variety of the proinflammatory genes linked to atherosclerosis. It was hypothesized that the inhibitory effects of adiponectin on the atherosclerosis is through the inhibition of NF-κB signaling pathway. We injected adenovirus of Ad-eGFP virus (control group) or the same amount of Ad-APN-eGFP virus (APN group) in ApoE-/- mice tail-intravenously. Blood samples and aorta were executed at 0 day, 4, and 8 week of high-fat diet feeding. Histopathological changes of aortic arch root were detected. Levels of TC, TG, HDL-C, LDL-C were measured. Adiponectin and Matrix metalloproteinases-9 (MMP-9) concentration were detected by enzyme-linked immunosorbent assay. Gene and protein levels of adiponectin, eNOS, IL-6, MCP-1,VCAM-1, and other inflammatory factors were determined. Adiponectin, NF-κB p65 in aortic arch root were determined by immunofluorescence and western blot. Transduction of Ad-APN inhibited the formation of atherosclerotic plaque in aorta when compared with control group. The lesion formation in aortic arch root was inhibited significantly (P < 0.01). Lesion lumen ratio decreased significantly (P < 0.001). The expression of adiponectin attenuated the increases of serum TC (P < 0.001), TG (P < 0.001), and LDL-C (P < 0.001) induced by the high-fat diet, and the increase in body weight (P < 0.05). As increasing serum adiponectin, the levels of MMP-9 were significantly decreased (P < 0.05). The exogenous adiponectin increased the gene expression of the anti-inflammatory factors eNOS (P < 0.05) and IL-10 (P < 0.001), and reduced the gene expression of inflammatory factors tumor necrosis factor-α (TNF-α) (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.05), respectively. Adiponectin effectively inhibited the activation of NF-κB pathway and the expression of NF-κB nuclear protein p65. Adiponectin may protect the aorta from atherosclerotic injury by reducing inflammation. The molecular mechanism may involve inhibited the expression of downstream components of NF-κB and its transcription factors.
Tài liệu tham khảo
Sessa R, Pietro MD, Filardo S, Turriziani O. Infectious burden and atherosclerosis: A clinical issue. World J Clin Cases. 2014;2:240–9.
Viola J, Soehnlein O. Atherosclerosis - A matter of unresolved inflammation. Semin Immunol. 2015;27(3):184–93.
Gao X, Xu XB, Belmadani S, Park Y, Tang ZH, Feldman AM, et al. TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol. 2007;27:1269–75.
Takeuchi S, Wada K, Uozumi Y, Otani N, Osada H, Nagatani K, et al. Adiponectin receptor 1 expression is associated with carotid plaque stability. Neurol India. 2013;61:249–53.
Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin receptors: A review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab. 2014;28:15–23.
van Stijn CMW, Kim J, Barish GD, Tietge UJF, Tangirala RK. Adiponectin expression protects against angiotensin II-mediated inflammation and accelerated atherosclerosis. Plos One. 2014;9(1):e86404.
Nakatsuji H, Kishida K, Sekimoto R, Komura N, Kihara S, Funahashi T, et al. Accumulation of adiponectin in inflamed adipose tissues of obese mice. Metabolism-Clinical and Experimental. 2014;63:542–53.
Fayad R, Pini M, Sennello JA, Cabay RJ, Chan L, Xu AM, et al. Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology. 2007;132:601–14.
Saijo S, Nagata K, Nakano Y, Tobe T, Kobayashi Y. Inhibition by adiponectin of IL-8 production by human macrophages upon coculturing with late apoptotic cells. Biochem Biophys Res Commun. 2005;334:1180–3.
Kobashi C, Urakaze M, Kishida M, Kibayashi E, Kobayashi H, Kihara S, et al. Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res. 2005;97:1245–52.
Nawrocki AR, Hofmann SM, Teupser D, Basford JE, Durand JL, Jelicks LA, et al. Lack of association between adiponectin levels and atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2010;30:1159–65.
Heo KS, Cushman HJ, Akaike M, Woo CH, Wang X, Qiu X, et al. ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation. 2014;130:180–91.
Lee S, Zhang H, Chen J, Dellsperger KC, Hill MA, Zhang C. Adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2012;303:H106–115.
Teupser D, Persky AD, Breslow JL. Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6 J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler Thromb Vasc Biol. 2003;23:1907–13.
Kempe S, Kestler H, Lasar A, Wirth T. NF-kappa B controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program. Nucleic Acids Res. 2005;33:5308–19.
Huang SS, Huang PH, Chen YH, Chiang KH, Chen JW, Lin SJ. Association of adiponectin with future cardiovascular events in patients after acute myocardial infarction. J Atheroscler Thromb. 2010;17:295–303.
Dagli N, Ozturk U, Karaca I, Yavuzkir M, Koca S, Akbulut H, et al. Adiponectin levels in coronary artery ectasia. Heart Vessel. 2009;24:84–9.
Lim S, Quon MJ, Koh KK. Modulation of adiponectin as a potential therapeutic strategy. Atherosclerosis. 2014;233:721–8.
Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C, et al. New insight into adiponectin role in obesity and obesity-related diseases. Biomed Research International. 2014;2014:658913.
Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2002;106:2767–70.
Wang XPH, Ma C, Jiang T, Wei Q, Zhang C, Duan M, et al. Adiponectin abates atherosclerosis by reducing oxidative stress. Med Sci Monit 2014. 2014;20:1792–800.
Zadelaar S, Kleemann R, Verschuren L, de Vries-Van der Weij J, van der Hoorn J, Princen HM, et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol. 2007;27:1706–21.
Sasaguri Y, Tanimoto A. Role of macrophage-derived histamine in atherosclerosis-- chronic participation in the inflammatory response. J Atheroscler Thromb. 2004;11:122–30.
Stafylas PC, Sarafidis PA, Lasaridis AN. The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality. Int J Cardiol. 2009;131:298–304.
Komura N, Maeda N, Mori T, Kihara S, Nakatsuji H, Hirata A, et al. Adiponectin protein exists in aortic endothelial cells. Plos One. 2013;8.
Mackesy DZ, Goalstone ML. Insulin augments tumor necrosis factor-alpha stimulated expression of vascular cell adhesion molecule-1 in vascular endothelial cells. J Inflamm (Lond). 2011;8:34.
Ohman MK, Shen Y, Obimba CI, Wright AP, Warnock M, Lawrence DA, et al. Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008;117:798–805.
Khan R, Spagnoli V, Tardif JC, L’Allier PL. Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis. 2015;240:497–509.
Blum A. HMG-CoA reductase inhibitors (statins), inflammation, and endothelial progenitor cells-New mechanistic insights of atherosclerosis. Biofactors. 2014;40:295–302.
Fischer S, Santos AN, Thieme R, Ramin N, Fischer B. Adiponectin stimulates glucose uptake in rabbit blastocysts. Biol Reprod. 2010;83:859–65.
Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993;92:883–93.
Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002;90:251–62.
Halade GV, Jin YF, Lindsey ML. Matrix metalloproteinase (MMP)-9: a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. Pharmacol Ther. 2013;139:32–40.
Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, et al. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res. 2002;91:852–9.
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G, et al. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia. 2010;53:1838–45.
Lee S, Park Y, Dellsperger KC, Zhang C. Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2011;301:H306–314.
Melgarejo E, Medina MA, Sanchez-Jimenez F, Urdiales JL. Monocyte chemoattractant protein-1: a key mediator in inflammatory processes. Int J Biochem Cell Biol. 2009;41:998–1001.
Thorp E, Kuriakose G, Shah YM, Gonzalez FJ, Tabas I. Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of nondiabetic low-density lipoprotein receptor-null mice. Circulation. 2007;116:2182–90.