Adiponectin alleviate blood hypercoagulability via inhibiting endothelial cell apoptosis induced by oxidative stress in septic rats

Document Type : Original Article


1 Department of Histology and Embryology, Binzhou Medical University, Yantai, P R China

2 Department of Critical Care Medicine, Yu Huang Ding Hospital, Qingdao University, Yantai, P R China

3 Department of Pathology, Yu Huang Ding Hospital, Qingdao University, Yan Tai, P R China


Objective(s): The purpose of this study was to detect the protective effects of adiponectin on coagulation dysfunction and its mechanism in sepsis of rats.
Materials and Methods: The experimental samples were composed of sham group,   model group that was underwent cecal ligation and puncture (CLP) and three adiponectin treatment groups that treated by adiponectin with different dose (72 μg/kg, 96 μg/kg and 120 μg/kg) after CLP. The prothrombin time (PT), activated partial thromboplastin time (APTT) was measured, respectively, the level of malondialdehyde (MDA), tissue factor (TF), activated coagulation factor VIIa and Xa, p-selectin were detected, the histology structure of vascular was observed, the expressions of Caspase 9, Caspase 3, Bax, Bcl-2 and vWF in vascular were measured.
Results: The results demonstrated that adiponectin treatment lengthened PT and APTT, reduced the expression of MDA, TF, activated coagulation factor VIIa, Xa and p-selectin in plasma of septic rats. Additionally, adiponectin treatment alleviated endothelial cell apoptosis and oxidative stress, down-regulated the levels of Caspase 3, Caspase 9, Bax, Bcl-2 and vWF in vascular.
Conclusion: These findings suggest that adiponectin treatment might be a promising therapeutic strategy for relieving septic endothelial cell injury and coagulation dysfunction via inhibiting endothelial cell apoptosis in septic rats.


Main Subjects

1.  Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. Br Med 2007; 335:879-883.
2.  Carrigan SD, Scott G, Tabrizian M. Toward resolving the challenges of sepsis diagnosis. Cli Chem 2004; 50:1301-1314.
3.  Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S, et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med 2006; 48: 28-54.
4.  Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al.  Nanchal R. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest J 2011; 140:1223-1231.
5.  Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001; 29: S109-S116.
6.  Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310.
7.  Vincent JL, De Backer D. Microvascular dysfunction as a cause of organ dysfunction in severe sepsis. Crit Care 2005; 9 Suppl 4:S9-12.
8.  Levi M, Poll T. Coagulation in patients with severe sepsis. SeminThromb Hemost 2015; 41: 9-15.
9.  Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129: 290-295.
10.  Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms insepsis. Nat Rev Immunol 2008; 8:776-787.
11.  Xu H, Ye X, Steinberg H, Liu SF. Selective blockade of endothelial NF-kappa B pathway differentially affects systemic inflammation and multiple organ dysfunction and injury in septic mice. J Pathol 2010; 220:490-498.
12.  Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity 2014; 40:463-475.
13.  Shi Y, Vanhoutte PM. Reactive oxygen-derived free radicals are keytothe endothelial dysfunction of diabetes. J Diabetes 2009; 1:151-162.
14.  Peters K, Unger RE, Brunner J, Kirkpatrick CJ. Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res 2003; 60:49-57.
15.  Trzeciak S, Cinel I, Phillip Dellinger R, Shapiro NI, Arnold RC, Parrillo JE, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008; 15:399-413.
16.  Carvalho PR, Trotta EA. Advances in sepsis diagnosis and treatment. J Pediatr 2003; 79 Suppl 2: S195-S204.
17.  Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348: 138-150.
18.  Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377.
19.  Nguyen HB, Rivers EP. The clinical practice of early goal-directed therapy in severe sepsis and septic shock. Adv Sepsis 2005; 4:126-133.
20.  Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784-1792.
21.  Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 2007; 9: 282-289.
22.  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: 2767-2770.
23.  Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, et al. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 2007; 117: 1718-1726.
24.  Tsuchihashi H, Yamamoto H, Maeda K, Ugi S, Mori T, Shimizu T, et al. Circulating concentrations of adiponectin, an endogenous lipopolysaccharide neutralizing protein, decrease in rats with polymicrobial sepsis. J Surg Res 2006; 134:348-353.
25.  Zhang L, Yao J, Wang X, Li H, Liu T, Zhao W. Poly (ADP-ribose) synthetase inhibitor has a heart protective effect in a rat model of experimental sepsis. Int J Clin Exp Pathol. 2015; 8:9824-9835.
26.  Zhang L, Wei J, Guo F, Duan J, Li Y, Shi Z, et al. Endosulfan activates the extrinsic coagulation pathway by inducing endothelial cell injury in rat. Environ Sci Pollut Res Int. 2015; 22:15722-15730.
27. Russell JA. Management of sepsis2006; 355:1699-1713.
28. Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol 2013; 11:150-160.
29. Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29 (7 Suppl):S28-34; discussion S-5.
30.  Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 2007; 100:158-173.
31.  Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 297 Suppl: S28-34; discussion S34-35.
32.  Pawlinski R, Mackman N. Cellular sources of tissue factor in endotoxemia and sepsis. Thromb Res 2010; 125 Suppl 1:S70-73.
33.  Taylor FB Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, et al. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-134.
34.  Guo R, Han M, Song J, Liu J, Sun Y. Adiponectin and its receptors are involved in hypertensive vascular injury. Mol Med Rep 2018; 17:209-215.
35.  Iacobellis G, Di Gioia C, Petramala L, Chiappetta C, Serra V, Zinnamosca L, et al. Brown fat expresses adiponectin in humans. Int J Endocrinol 2013; 2013: 126751.
36.  Tsuchihashi H, Yamamoto H, Maeda K, Ugi S, Mori T, Shimizu T, et al. Circulating concentrations of adiponectin, an endogenous lipopolysaccharide neutralizing protein, decrease in rats with polymicrobial sepsis. J Surg Res 2006; 134:348-353.
37.  Teoh H, Quan A, Ban KW, Wang G, Lovren F, Vu V, et al. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab 2008; 295:E658-664.
38.  van Meurs M, Castro P, Shapiro NI, Lu S, Yano M, Maeda N, et al. Adiponectin diminishes organ-specific microvascular endothelial cell activation associated with sepsis. Shock 2012; 37:392-398.
39.  LV, Pendurthi UR. Regulation of tissue factor coagulant activityon cell surfaces. J Thromb Haemost 2012; 10:2242-2253.
40.  Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem1988;   57:915-956.
41.  KoklicT, Majumder R, Lentz BR. Ca2+ switches the effect of PS-containing membranes on factor Xa from activating to inhibiting: implications for initiation of blood coagulation. Biochem J 2014; 462:591-601.
42.  Reininger AJ, Heijnen HF, Schumann H, Specht HM, Schramm W, Ruggeri ZM. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation  under high shear stress. Blood 2006; 107:3537-3545.
43.  Jurd KM, Stephens CJ, Black MM, Hunt BJ. Endothelial cell activation in cutaneous vasculitis. Clin Exp Dermatol 1996; 21:28-32.
44.  Breitenstein A, Sluka SH, Akhmedov A, Stivala S, Steffel J, Camici GG, et al. Dronedarone reduces arterial thrombus formation. Basic Res Cardiol 2012; 107:302.
45.  Schletter J, Heine H, Ulmer AJ, Rietschel ET. Molecular mechanisms of endotoxin activity. Arch Microbiol 1995; 164:383-389.
46.  Goode HF, Webster NR. Free radicals and antioxidants in sepsis. Crit Care Med 1994; 21:1770-1776.
47.  Koksal GM, Sayilgan C, Aydin S, Oz H, Uzun H. Correlation of plasma and tissue oxidative stresses in intra-abdominal sepsis. J Surg Res 2004; 122: 180‑183.
48. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18:621-663.
49. Zaki OS, Safar MM, Ain-Shoka AA, Rashed LA. A novel role of a chemotherapeutic agent in a rat model of endotoxemia: modulation of the STAT-3 signaling pathway. Inflammation 2018; 41:20-32.
50.  Cai Y, Zou Z, Liu L, Chen S, Chen Y, Lin Z, et al. Bone marrow-derived mesenchymal stem cells inhibits hepatocyte apoptosis after acute liver injury. Int J Clin Exp Pathol 2015; 8: 107-116.
51.  Cui WY, Tian AY, Bai T. Protective effects of propofolon endotoxemia induced acute kidney injury in rats. Clin Exp Pharmacol Physiol 2011; 38: 747-754.
52. Demiralay R, Gursan N, Erdem H. The effects of erdosteine and N-acetylcysteine on apoptotic and antiapoptotic markers in pulmonary epithelial cells in sepsis. Eurasian J Med 2013; 45: 167-175.
53.  Li X, Guo H, Zhao L, Wang B, Liu H, Yue L, et al. Adiponectin attenuates NADPH oxidase-mediated oxidative stress and neuronal damage induced by cerebral ischemia-reperfusion injury. Biochim Biophys Acta 2017; 1863:3265-3276.