Enhanced Inflammatory Reaction and Thrombosis
                                                  in High-Fat Diet-Fed ApoE-/- Mice are
                                                  Attenuated by Celastrol

Mao Ouyang; Tao Qin; Hengdao Liu; Junya Lu; Caixia Peng; Qin Guo

doi:10.1055/a-1010-5543

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2021; 129(05): 339-348
DOI: 10.1055/a-1010-5543

Article

Enhanced Inflammatory Reaction and Thrombosis in High-Fat Diet-Fed ApoE^-/- Mice are Attenuated by Celastrol

Mao Ouyang

¹Department of Geriatrics, the Third Xiangya Hospital, Central South University, Changsha, P. R. China

,

Tao Qin

¹Department of Geriatrics, the Third Xiangya Hospital, Central South University, Changsha, P. R. China

,

Hengdao Liu

¹Department of Geriatrics, the Third Xiangya Hospital, Central South University, Changsha, P. R. China

²Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China

,

Junya Lu

¹Department of Geriatrics, the Third Xiangya Hospital, Central South University, Changsha, P. R. China

,

Caixia Peng

¹Department of Geriatrics, the Third Xiangya Hospital, Central South University, Changsha, P. R. China

,

Qin Guo

³Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, P. R. China

› Author Affiliations

Abstract

Objective High-fat diet (HFD) increases the risk of inflammatory reaction and acute arterial thrombosis. Celastrol has been confirmed to regulate inflammatory cytokine levels in atherosclerotic animal models. However, the anti-thrombotic effects of celastrol have remained to be fully demonstrated. The present study was performed to investigate the beneficial effect of celastrol in HFD-induced inflammatory reaction and thrombosis in apolipoprotein (apo)E^-/- mice.

Materials and Methods Thrombogenic mice model was established using HFD-fed apoE^-/- mice. The levels of mRNA and protein were assayed by RT-qPCR and western blotting, respectively. Immunohistochemistry (IHC) staining was performed to measure the protein expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the aortic endothelium of HFD-fed apoE^-/- mice.

Results The results demonstrated that the effect of HFD on inflammatory cytokines in mice with apoE^-/- background was reversed by celastrol administration, and celastrol treatment inhibited the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1/interleukin-1β signaling cascades in peripheral blood mononuclear cells from HFD-fed apoE^-/- mice. In addition, HFD enhanced adenosine diphosphate-induced platelet aggregation in normal C57BL/6 and apoE^-/- mice, while celastrol administration reversed this. Furthermore, celastrol inhibited the pro-thrombotic effects of HFD in apoE^-/- mice, and the underlying mechanism was mediated, at least partially, through the suppression of matrix metalloproteinase-2 and -9 expression.

Conclusions Celastrol administration significantly attenuated HFD-induced inflammatory reaction, platelet aggregation and thrombosis in apoE^-/- mice, and celastrol may be used as a drug for the prevention of HFD-induced inflammatory reaction and thrombus.

Key words

thrombus - inflammation - celastrol - matrix metalloproteinase - NLRP3

Full Text

References

References
1 Sharda A, Kim SH, Jasuja R. et al. Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood 2015; 125: 1633-1642
2 Cui G, Shan L, Guo L. et al. Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy. Scientific Reports 2015; 5: 10353
3 Yu C, Qi D, Lian W. et al. Effects of danshensu on platelet aggregation and thrombosis: In vivo arteriovenous shunt and venous thrombosis models in rats. PloS One 2014; 9: e110124
4 Darvall KA, Sam RC, Silverman SH. et al. Obesity and thrombosis. European journal Of Vascular and Endovascular Surgery: The Official Journal of the European Society for. Vascular Surgery 2007; 33: 223-233
5 Samad F, Ruf W. Inflammation, obesity, and thrombosis. Blood 2013; 122: 3415-3422
6 Li Y, CGZ Wang XH. et al. Progression of atherosclerosis in ApoE-knockout mice fed on a high-fat diet. European Review for Medical and Pharmacological Sciences 2016; 20: 3863-3867
7 Wen H, Gris D, Lei Y. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunology 2011; 12: 408-415
8 Kim K, Hahm E, Li J. et al. Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice. Blood 2013; 122: 1052-1061
9 Cho J, Furie BC, Coughlin SR. et al. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. The Journal of Clinical Investigation 2008; 118: 1123-1131
10 Astry B, Venkatesha SH, Laurence A. et al. Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ. Clinical Immunology (Orlando, Fla) 2015; 157: 228-238
11 Li H, Zhang YY, Huang XY. et al. Beneficial effect of tripterine on systemic lupus erythematosus induced by active chromatin in BALB/c mice. European Journal of Pharmacology 2005; 512: 231-237
12 Liu J, Lee J, Salazar Hernandez MA. et al. Treatment of obesity with celastrol. Cell 2015; 161: 999-1011
13 Ma X, Xu L, Alberobello AT. et al. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1alpha transcriptional axis. Cell Metabolism 2015; 22: 695-708
14 Kim JE, Lee MH, Nam DH. et al. Celastrol, an NF-kappaB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PloS One 2013; 8: e62068
15 Yang L, Li Y, Ren J. et al. Celastrol attenuates inflammatory and neuropathic pain mediated by cannabinoid receptor type 2. International Journal of Molecular Sciences 2014; 15: 13637-13648
16 Zennadi R, Chien A, Xu K. et al. Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood 2008; 112: 3474-3483
17 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 2001; 25: 402-408
18 Gong J, Wang ZX, Liu ZY. miRNA1271 inhibits cell proliferation in neuroglioma by targeting fibronectin 1. Molecular Medicine Reports 2017; 16: 143-150
19 Abderrazak A, Couchie D, Mahmood DF. et al. Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet. Circulation 2015; 131: 1061-1070
20 Kuida K, Lippke JA, Ku G. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science (New York, NY) 1995; 267: 2000-2003
21 Sood V, Luke C, Miller E. et al. Vein wall remodeling after deep vein thrombosis: differential effects of low molecular weight heparin and doxycycline. Annals of Vascular Surgery 2010; 24: 233-241
22 Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Letters 2011; 303: 9-20
23 Allison AC, Cacabelos R, Lombardi VR. et al. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s disease. Progress in Neuro-psychopharmacology & Biological Psychiatry 2001; 25: 1341-1357
24 Kang SW, Kim MS, Kim HS. et al. Celastrol attenuates adipokine resistin-associated matrix interaction and migration of vascular smooth muscle cells. Journal of Cellular Biochemistry 2013; 114: 398-408
25 Han LP, Li CJ, Sun B. et al. Protective effects of celastrol on diabetic liver injury via TLR4/MyD88/NF-kappaB Signaling pathway in type 2 diabetic rats. Journal of Diabetes Research 2016; 2016: 2641248
26 Ju SM, Youn GS, Cho YS. et al. Celastrol ameliorates cytokine toxicity and pro-inflammatory immune responses by suppressing NF-kappaB activation in RINm5F beta cells. BMB Reports 2015; 48: 172-177
27 Gu L, Bai W, Li S. et al. Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress. PloS One 2013; 8: e65477
28 Li M, Liu X, He Y. et al. Celastrol attenuates angiotensin II mediated human umbilical vein endothelial cells damage through activation of Nrf2/ERK1/2/Nox2 signal pathway. European Journal of Pharmacology 2017; 797: 124-133
29 Siefert SA, Chabasse C, Mukhopadhyay S. et al. Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice. Journal of Thrombosis and Haemostasis: JTH 2014; 12: 1706-1716
30 Kohashi K, Hiromura M, Mori Y. et al. A Dipeptidyl Peptidase-4 Inhibitor but not incretins suppresses abdominal aortic aneurysms in angiotensin II-Infused apolipoprotein E-Null mice. Journal of Atherosclerosis and Thrombosis 2016; 23: 441-454
31 Li G, Liu D, Zhang Y. et al. Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-kappaB-mediated matrix metalloproteinase-9 expression. PloS One 2013; 8: e68905
32 Li X, de Boer OJ, Ploegmaker H. et al. Granulocytes in coronary thrombus evolution after myocardial infarction--time-dependent changes in expression of matrix metalloproteinases.. Cardiovascular pathology The Official Journal of the Society for Cardiovascular Pathology 2016; 25: 40-46
33 Khan JA, Abdul Rahman MN, Mazari FA. et al. Intraluminal thrombus has a selective influence on matrix metalloproteinases and their inhibitors (tissue inhibitors of matrix metalloproteinases) in the wall of abdominal aortic aneurysms. Annals of Vascular Surgery 2012; 26: 322-329
34 Wang X, Chen Q, Pu H. et al. Adiponectin improves NF-kappaB-mediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice. Lipids in Health and Disease 2016; 15: 33
35 Zhu H, Dai R, Zhou Y. et al. TLR2 ligand Pam3CSK4 regulates MMP-2/9 expression by MAPK/NF-kappaB signaling pathways in primary brain microvascular endothelial cells. Neurochemical Research 2018; 43: 1897-1904
36 Ding XW, Sun X, Shen XF. et al. Propofol attenuates TNF-alpha-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca(2+)/CAMK II/ERK/NF-kappaB signaling pathway. Acta pharmacologica Sinica 2019; 40: 1303-1313

Enhanced Inflammatory Reaction and Thrombosis in High-Fat Diet-Fed ApoE-/- Mice are Attenuated by Celastrol

Enhanced Inflammatory Reaction and Thrombosis in High-Fat Diet-Fed ApoE^-/- Mice are Attenuated by Celastrol