Urocortin对糖尿病心肌病的保护作用与Akt/GSK-3β信号通路的关系
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摘要
目的观察内分泌-血管活性肽Urocortin(UCN)对糖尿病心肌病(DCM)大鼠TGF-β1和CTGF的影响,研究UCN对DCM的保护作用及可能机制。方法建立糖尿病(DM)模型,将大鼠分为5组:Control组、DCM组、UCN组、UCN+Astressin组、UCN+Triciribine组。饲养12周后处理4周,测定血糖、尿糖、尿量,以及血清TGF-β1、CTGF水平;观察心肌细胞形态学;测定心肌组织TGF-β1、CTGT、Akt、GSK-3β、pAkt、p-GSK-3β的表达。结果 DM大鼠心肌形态学符合DCM改变,与Control组相比,DCM组血清与心肌组织TGF-β1、CTGF水平均增高,DCM组心肌组织p-Akt、p-GSK-3β均降低(P <0. 05)。与DCM组相比,UCN组TGF-β1、CTGF水平均降低(P <0. 05),Astressin和Triciribine均能阻断UCN的作用(P <0. 05); UCN组p-Akt、p-GSK-3β表达增高(P <0. 05),Astressin阻断UCN的作用(P <0. 05)。结论 UCN对DCM的保护作用可能通过与CRH-R受体结合后,激活Akt/GSK-3β信号通路,下调炎症因子TGF-β1及CTGF的表达有关。
Aim To observe the effects of UCN on TGF-β1 and CTGF in rats with DCM,and to explore the protective effects of UCN on DCM and its possible signaling pathway. Methods The rats were divided into five groups: control group, DCM group, UCN group,UCN + Astressin group,and UCN + Triciribine group. After 12 weeks of feeding and 4 weeks of treatment,blood glucose,urinary sugar,urine volume and the levels of TGF-β1,CTGF in serum were determined,and the expression of TGF-β1,CTGF,Akt,GSK-3β,p-Akt and p-GSK-3β of cardiomyocytes were also determined. Results The myocardial HE staining in DM rats was consistent with DCM. The levels of TGF-β1 and CTGF in serum and myocardium of rats with DCM increased significantly,while the levels of p-Akt and p-GSK-3β in myocardium of rats with DCM decreased significantly( P < 0. 05). The levels of TGF-β1 and CTGF in UCN group decreased,both astressin and triciribine could inhibit the role of UCN,and the expression of p-Akt and p-GSK-3β in myocardial cells in UCN group increased significantly,then astressin could inhibit the role of UCN( P < 0. 01).Conclusions The protective effects of UCN on DCM might be related to the activation of Akt/GSK-3β signaling pathway after binding with CRH-R receptor,and then decreasing the expression of TGF-β1 and CTGF.
Aim To observe the effects of UCN on TGF-β1 and CTGF in rats with DCM,and to explore the protective effects of UCN on DCM and its possible signaling pathway. Methods The rats were divided into five groups: control group, DCM group, UCN group,UCN + Astressin group,and UCN + Triciribine group. After 12 weeks of feeding and 4 weeks of treatment,blood glucose,urinary sugar,urine volume and the levels of TGF-β1,CTGF in serum were determined,and the expression of TGF-β1,CTGF,Akt,GSK-3β,p-Akt and p-GSK-3β of cardiomyocytes were also determined. Results The myocardial HE staining in DM rats was consistent with DCM. The levels of TGF-β1 and CTGF in serum and myocardium of rats with DCM increased significantly,while the levels of p-Akt and p-GSK-3β in myocardium of rats with DCM decreased significantly( P < 0. 05). The levels of TGF-β1 and CTGF in UCN group decreased,both astressin and triciribine could inhibit the role of UCN,and the expression of p-Akt and p-GSK-3β in myocardial cells in UCN group increased significantly,then astressin could inhibit the role of UCN( P < 0. 01).Conclusions The protective effects of UCN on DCM might be related to the activation of Akt/GSK-3β signaling pathway after binding with CRH-R receptor,and then decreasing the expression of TGF-β1 and CTGF.
引文
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[13] Ersahin T,Tuncbag N,Cetin-Atalay R. The PI3K/AKT/m TOR interactive pathway[J]. Mol Biosyst,2015,11(7):1946-54.
[14] Wang Y,Yang R,Gu J,et al. Cross talk between PI3K-AKTGSK-3βand PP2A pathways determines tau hyperphosphorylation[J]. Neurobiol Aging,2015,36(1):188-200.
[15] Zhang Y,Huang N Q,Yan F,et al. Diabetes mellitus and Alzheimer's disease:GSK-3βas a potential link[J]. Behav Brain Res,2018,339:57-65.
[16] Karteris E,Vatish M,Hillhouse E W J,et al. Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by corticotropin-releasing hormone(CRH)and CRH-related peptides[J]. Clin Endocrinol Metab,2005,90(6):3680-7.
[17] Lai N C,Gao M H,Giamouridis D,et al. Intravenous AAV8 encoding urocortin-2 increases function of the failing heart in mice[J]. Hum Gene Ther,2015,26(6):347-56.
[2] Guo R,Nair S. Role of microRNA in diabetic cardiomyopathy:from mechanism to intervention[J]. Biochim Biophys Acta Mol Basis Dis,2017,1863(8):2070-7.
[3] Sukumaran V,Tsuchimochi H,Tatsumi E,et al. Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade[J]. Biochem Pharmacol,2017,144:90-9.
[4] Stirrat C G,Venkatasubramanian S,Pawade T,et al. Cardiovascular effects of urocortin 2 and urocortin 3 in patients with chronic heart failure[J]. Br J Clin Pharmacol,2016,82(4):974-82.
[5] Monteiro-Pinto C,Mulvaney E P,Reid H M,et al. Urocortin-2improves right ventricular function and attenuates pulmonary arterial hypertension[J]. Cardiovasc Res,2018,114(8):1165-77.
[6] Gauer S,Holzmann Y,Krnzlin B,et al. CTGF is expressed during cystic remodeling in the PKD/Mhm(cy/+)rat model for autosomal-dominant polycystic kidney disease(ADPKD)[J]. J Histochem Cytochem,2017,65(12):743-55.
[7] Ren Y,Du C,Shi Y,et al. The Sirt1 activator,SRT1720,attenuates renal fibrosis by inhibiting CTGF and oxidative stress[J].Int J Mol Med,2017,39(5):1317-24.
[8] Cheng J C,Chang H M,Leung P C K. Connective tissue growth factor mediates TGF-β1-induced low-grade serous ovarian tumor cell apoptosis[J]. Oncotarget,2017,8(49):85224-33.
[9] Delaney K,Kasprzycka P,Ciemerych M A. The role of TGF-β1during skeletal muscle regeneration[J]. Cell Biol Int,2017,41(7):706-15.
[10] Chen J T,Wang C Y,Chen M H. Curcumin inhibits TGF-β1-induced connective tissue growth factor expression through the interruption of Smad2 signaling in human gingival fibroblasts[J]. J Formos Med Assoc,2018,117(12):1115-23.
[11] Liu X,Liu C,Li J,et al. Urocortin attenuates myocardial fibrosis in diabetic rats via the Akt/GSK-3βsignaling pathway[J]. Endocr Res,2016,41(2):148-57.
[12]柯旋,李宾公,郝艳琴,等. Vaspin在糖尿病心肌病中的作用及机制研究[J].中国药理学通报,2018,34(10):1403-8.[12] Ke X,Li B G,Hao Y Q,et al. Role and mechanism of vaspin in diabetic cardiomyopathy[J]. Chin Pharmacol Bull,2018,34(10):1403-8.
[13] Ersahin T,Tuncbag N,Cetin-Atalay R. The PI3K/AKT/m TOR interactive pathway[J]. Mol Biosyst,2015,11(7):1946-54.
[14] Wang Y,Yang R,Gu J,et al. Cross talk between PI3K-AKTGSK-3βand PP2A pathways determines tau hyperphosphorylation[J]. Neurobiol Aging,2015,36(1):188-200.
[15] Zhang Y,Huang N Q,Yan F,et al. Diabetes mellitus and Alzheimer's disease:GSK-3βas a potential link[J]. Behav Brain Res,2018,339:57-65.
[16] Karteris E,Vatish M,Hillhouse E W J,et al. Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by corticotropin-releasing hormone(CRH)and CRH-related peptides[J]. Clin Endocrinol Metab,2005,90(6):3680-7.
[17] Lai N C,Gao M H,Giamouridis D,et al. Intravenous AAV8 encoding urocortin-2 increases function of the failing heart in mice[J]. Hum Gene Ther,2015,26(6):347-56.