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DOI: 10.1055/s-0038-1676987
Deep Vein Thrombosis is Modulated by Inflammation Regulated via Sirtuin 1/NF-κB Signalling Pathway in a Rat Model
Funding This work was supported by Guangdong Public Welfare Research and Capacity Building Projects (2016A020217016).Publication History
07 September 2018
18 November 2018
Publication Date:
07 January 2019 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201903/lookinside/thumbnails/10-1055-s-0038-1676987_180647-1.jpg)
Abstract
Background Inflammation plays an important role in thrombus formation, and Sirtuin 1 (SIRT1) negatively regulates inflammation via deacetylating nuclear factor-kappa B. However, the relationship between SIRT1-regulated inflammation and deep vein thrombosis (DVT) is still unknown.
Objective The aim of this study was to investigate whether SIRT1 plays a critical role in inferior vena cava (IVC) stenosis-induced DVT.
Materials and Methods Thrombus weight and histopathologic analysis of IVC were evaluated at different time points after IVC stenosis in rats. Serum levels of inflammatory cytokines and protein expressions of SIRT1, acetylated p65 (Ace-p65), phosphorylated p65 (p-p65) and tissue factor (TF) in thrombosed IVC were assessed. Besides, the effects of resveratrol (RES, a SIRT1 agonist) and EX527 (a selective SIRT1 inhibitor) on DVT were evaluated.
Results Thrombus weight was increased from 1 to 3 days after IVC stenosis, and then was decreased afterwards. Leukocytes infiltration appeared and serum levels of cytokines were significantly increased in rats of IVC stenosis. SIRT1 protein expression was significantly down-regulated at 1 hour and 1 day after stenosis, while p-p65, Ace-p65 and TF protein expressions appeared a contrary trend. RES reduced thrombus weight, leukocytes infiltration, levels of tumour necrosis factor-α and interleukin-1β and protein expressions of Ace-p65 and TF as well. Moreover, RES significantly increased the protein and messenger ribonucleic acid expressions of SIRT1, while EX527 abolished the protective effects of RES.
Conclusion SIRT1 activation attenuated IVC stenosis-induced DVT via anti-inflammation in rats. Therefore, SIRT1 may be a potential therapeutic target that could ameliorate DVT.
Authors' Contributions
Baoqin Lin designed the research studies. Xaolan Yao performed the experiment and wrote the manuscript. Wenpei Chen, Jin Liu, Han Liu, Janis Y. Zhan, Shixia Guan, Ziqi Lu, Ping Tang and Peng Li analysed and interpreted data. All authors revised the manuscript and approved the final version.
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References
- 1 Di Minno MN, Ambrosino P, Ambrosini F, Tremoli E, Di Minno G, Dentali F. Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2016; 14 (05) 964-972
- 2 Bawa H, Weick JW, Dirschl DR, Luu HH. Trends in deep vein thrombosis prophylaxis and deep vein thrombosis rates after total hip and knee arthroplasty. J Am Acad Orthop Surg 2018; 26 (19) 698-705
- 3 Glynn RJ, Ridker PM. Inflammation, venous thromboembolism, and what we can do about it. Eur Heart J 2018; 39 (39) 3615-3617
- 4 Wang LM, Duan QL, Yang F. , et al. Activation of circulated immune cells and inflammatory immune adherence are involved in the whole process of acute venous thrombosis. Int J Clin Exp Med 2014; 7 (03) 566-572
- 5 Saghazadeh A, Rezaei N. Inflammation as a cause of venous thromboembolism. Crit Rev Oncol Hematol 2016; 99: 272-285
- 6 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
- 7 Schulz C, Engelmann B, Massberg S. Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J Thromb Haemost 2013; 11 (Suppl. 01) 233-241
- 8 Zhang Z, Hu L, Chen W, Zhou C, Gui G, Lin B. Danhong huayu koufuye prevents deep vein thrombosis through anti-inflammation in rats. J Surg Res 2016; 201 (02) 340-347
- 9 Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128 (06) 753-762
- 10 Saha P, Humphries J, Modarai B. , et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011; 31 (03) 506-512
- 11 Pikarsky E, Porat RM, Stein I. , et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004; 431 (7007): 461-466
- 12 Malaponte G, Signorelli SS, Bevelacqua V. , et al. Increased levels of NF-κB-dependent markers in cancer-associated deep venous thrombosis. PLoS One 2015; 10 (07) e0132496
- 13 Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J 2007; 404 (01) 1-13
- 14 Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006; 20 (21) 2913-2921
- 15 Liu TF, Vachharajani VT, Yoza BK, McCall CE. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 2012; 287 (31) 25758-25769
- 16 Yoshizaki T, Milne JC, Imamura T. , et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 2009; 29 (05) 1363-1374
- 17 Breitenstein A, Stein S, Holy EW. , et al. Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. Cardiovasc Res 2011; 89 (02) 464-472
- 18 Hayashi H, Cherpokova D, Martinod K. , et al. Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice. PLoS One 2017; 12 (12) e0188341
- 19 de Lange P, Cioffi F, Senese R. , et al. Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats. Diabetes 2011; 60 (11) 2730-2739
- 20 Zhang H, Yan H, Zhou X. , et al. The protective effects of Resveratrol against radiation-induced intestinal injury. BMC Complement Altern Med 2017; 17 (01) 410
- 21 Nosaka M, Ishida Y, Kimura A, Kondo T. Time-dependent appearance of intrathrombus neutrophils and macrophages in a stasis-induced deep vein thrombosis model and its application to thrombus age determination. Int J Legal Med 2009; 123 (03) 235-240
- 22 Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003; 1 (07) 1343-1348
- 23 Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005; 15 (07) 254-259
- 24 Scaldaferri F, Sans M, Vetrano S. , et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117 (07) 1951-1960
- 25 Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res 2005; 96 (12) 1233-1239
- 26 Nishimura S, Manabe I, Nagasaki M. , et al. In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling. Blood 2012; 119 (08) e45-e56
- 27 Chu AJ. Tissue factor mediates inflammation. Arch Biochem Biophys 2005; 440 (02) 123-132
- 28 Gillum MP, Kotas ME, Erion DM. , et al. SirT1 regulates adipose tissue inflammation. Diabetes 2011; 60 (12) 3235-3245
- 29 Cao L, Liu C, Wang F, Wang H. SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway. Braz J Med Biol Res 2013; 46 (08) 659-669
- 30 Li J, Li L, Wang S. , et al. Resveratrol alleviates inflammatory responses and oxidative stress in rat kidney ischemia-reperfusion injury and H2O2-induced NRK-52E cells via the Nrf2/TLR4/NF-κB pathway. Cell Physiol Biochem 2018; 45 (04) 1677-1689
- 31 Xu M, Cheng Z, Ding Z, Wang Y, Guo Q, Huang C. Resveratrol enhances IL-4 receptor-mediated anti-inflammatory effects in spinal cord and attenuates neuropathic pain following sciatic nerve injury. Mol Pain 2018; 14: 1744806918767549
- 32 Zhao H, Chen S, Gao K. , et al. Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience 2017; 348: 241-251
- 33 Timmers S, Auwerx J, Schrauwen P. The journey of resveratrol from yeast to human. Aging (Albany NY) 2012; 4 (03) 146-158
- 34 Sin TK, Yung BY, Yip SP. , et al. SIRT1-dependent myoprotective effects of resveratrol on muscle injury induced by compression. Front Physiol 2015; 6: 293
- 35 Tong Z, Xie Y, He M. , et al. VDAC1 deacetylation is involved in the protective effects of resveratrol against mitochondria-mediated apoptosis in cardiomyocytes subjected to anoxia/reoxygenation injury. Biomed Pharmacother 2017; 95: 77-83
- 36 Xu S, Gao Y, Zhang Q. , et al. SIRT1/3 activated by resveratrol attenuates acute kidney injury in a septic rat model. Oxid Med Cell Longev 2016; 2016: 7296092
- 37 Liu J, Han W, Chen L, Tang K. Mechanism of osteogenic and adipogenic differentiation of tendon stem cells induced by sirtuin 1. Mol Med Rep 2016; 14 (02) 1643-1648
- 38 Guo H, Chen Y, Liao L, Wu W. Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway. Cardiovasc Drugs Ther 2013; 27 (03) 189-198