Alteration of Wnt/β-catenin signaling pathway in type 2 diabetic rats' aorta and regulation of SIRT1
(2.School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China 250062)
(3.China Pharmaceutical University, Nanjing, China 211198)
【Abstract】 Aim To investigate the alteration of Wnt/β-catenin signaling and sirtuins 1 in type 2 diabetic rats' aorta and clarify its role in the development of diabetes aortic disease. Methods The type 2 diabetic rat model was established by injection of streptozocin after five-week of high fat diet. The rats were randomly divided into control group, DM model group of 2 weeks, 4 weeks, 8 weeks and 12 weeks. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and fasting insulin (FINS) levels were tested. HE staining was used to observe the pathological changes of aortal structures. The alteration of Wnt2, β-catenin, TCF4, SIRT1 and sFRP2 in aorta was determined by Western blot and RT-PCR. Results Compared with control group, TC, TG, LDL-C levels of type 2 diabetic rats were significantly increased, HDL-C levels were significantly reduced (P < 0.01). Aortic histological analysis revealed that DM induced aortic endothelial cell vacuolar degeneration and necrosis. The expression of Wnt2 and β-catenin level increased significantly in the first 4 weeks of diabetic groups compared to control group, and that in model group of 8 weeks and 12 weeks kept in the high level and showed no significant alteration (P > 0.05). But the expression of TCF4 and SIRT1 was enhanced continuously in DM compared with control group while sFRP2 decreased in the duration of DM development. Conclusions Wnt/β-catenin signaling pathway was activated in diabetic aorta injury by regulation of SIRT1 via sFRP2. Further researches on its mechanism of action in DM aorta injury may find a new therapeutic target for the disease.
【Keywords】 Wnt2; β-catenin; TCF4; SIRT1; sFRP2; type 2 diabetes; aorta injury;
Zhuang Y, Mao J Q, Yu M, et al. Hyperlipidemia induces vascular smooth muscle cell proliferation involving Wnt/β-catenin signaling[J]. Cell Biol Int, 2016, 40(2): 121-30.
Xi X H, Wang Y, Li J, et al. Activation of Wnt/β-catenin/GSK3βsignaling during the development of diabetic cardiomyopathy[J]. Cardiovasc Pathol, 2015, 24(3): 179-86.
Singh R, Smith E, Fathzadeh M, et al. Rare nonconservative LRP6 mutations are associated with metabolic syndrome[J]. Hum Mutat, 2013, 34(9): 1221-5.
Wang W R, Liu E Q, Zhang J Y, et al. Activation of PPAR alpha by fenofibrate inhibits apoptosis in vascular adventitial fibroblasts partly through SIRT1-mediated deacetylation of FoxO 1[J]. Exp Cell Res, 2015, 338(1): 54-63.
Kim Y H, Bae J U, Lee S J, et al. SIRT1 attenuates PAF-induced MMP-2 production via down-regulation of PAF receptor expression in vascular smooth muscle cells[J]. Vascul Pharmacol, 2015, 72: 35-42.
Rhee K J, Lee C G, Kim S W, et al. Extract of Ginkgo Biloba A-meliorates streptozotocin-induced type 1 diabetes mellitus and high-fat diet-induced type 2 diabetes mellitus in mice[J]. Int JMed Sci, 2015, 12(12): 987-94.
Blankesteijn W M, Hermans K. Wnt signaling in atherosclerosis[J]. Eur J Pharmacol, 2015, 763(Part A): 122-30.
Dabernat S, Secrest P, Peuchant E, et al. Lack of beta-catenin in early life induces abnormal glucose homeostasis in mice[J]. Diabetologia, 2009, 52(8): 1608-17.
Yan Z, Yao F, Zhang L P, et al. Modulation of Wnt/β-catenin signaling pathway byirbesartan in high glucose induced tubular epithelial mesenchymal transition[J]. Chin Pharmacol Bull, 2009, 25(12): 1630-4 (in Chinese).
Xi X H, Wang F W, Wang Y, et al. Alteration of Wnt/β-catenin signaling pathway in early diabetic rats'myocardium[J]. Chin Pharmacol Bull, 2015, 31(3): 363-6 (in Chinese).
Takeda W A, Kitada M, Kanasaki K, et al. SIRT1 in activation induces inflammation through the dysregulation of autophagy in human THP-1 cells[J]. Biochem Biophys Res Commun, 2012, 427(1): 191-6.
Yang Z, Kahn B B, Shi H, et al. Macrophage alpha1 AMP-activated protein kinase(alpha1 AMPK)antagonizes fatty acid-induced inflammation through SIRT1[J]. J Biol Chem, 2010, 285(25): 19051-9.
Liu B, Zhang R, Tao G, et al. Augmented wnt-signaling as a therapeutic tool to prevent ischemia and reperfusion injury in liver: preclinical studies in a mouse model[J]. Liver Transpl, 2015, 21(12): 1533-42.
Zhou Y, Zhou Z, Zhang W, et al. SIRT1 inhibits adipogenesis and promotes myogenic differentiation in C3H10T1/2 pluripoten cells by regulating Wnt signaling[J]. Cell Biosci, 2015, 5: 61.
Dawson K, Aflaki M, Nattel S. Role of the wnt-frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential[J]. J Physiol, 2013, 591(6): 1409-32.