激活TGR5通过抑制CaN/NAFT3减轻ET-1诱导的心肌细胞肥大
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摘要
目的观察G蛋白偶联胆汁酸受体1(G protein-coupled bile acid receptor 1,TGR5)受体激活后对内皮素-1(endothelin-1,ET-1)诱导心肌细胞肥大的作用及其机制的探讨。方法原代培养乳鼠心肌细胞,分为空白对照组和ET-1组,ET-1组的浓度分别为10~(-6)、10~(-7)、10~(-8) mmol/L,分别培养12、24、36、48 h,分别检测各组心肌细胞表面积和总蛋白浓度,建立心肌肥大细胞模型。将心肌细胞分为对照组、ET-1组、ET-1+INT-777(TGR5受体激动剂)组、ET-1+INT-777+TGR5 siRNA(干扰TGR5表达)组、ET-1+INT-777+TGR5 siRNA-NC(空病毒)组。采用图像分析系统测定心肌细胞表面积,BCA法测定细胞总蛋白量,RT-PCR检测TGR5、钙调神经磷酸酶(calcineurin,CaN)的mRNA,Western blot方法检测心房尿钠因子(atrial natriuretic factor,ANF)、β-肌球蛋白重链(β-myosin heavy chain,β-MHC)、TGR5、CaN、活化T细胞核因子3(activated T cell nuclear factor 3,NFAT3)的蛋白表达变化。结果 48 h内,ET-1诱导心肌细胞肥大在10~(-8) mmol/L～10~(-6) mmol/L浓度范围内成明显浓度依赖性和时间依赖性(P<0.05),其中ET-1 10~(-6) mmol/L培养48 h心肌细胞表面积为(3 624.7±71.60)um~2,总蛋白量(51.810±1.47)μg,显著高于对照组表面积(1 560.8±3 188.94)um~2和总蛋白(37.827±0.47)μg(P<0.05)。与对照组相比,ET-1组心肌细胞表面积、总蛋白、ANF及β-MHC表达增加(P<0.05),CaN及NFAT3的表达增加(P<0.05)。与ET-1组心肌细胞表面积(4 167.59±271.11)um~2、总蛋白(57.765±0.553)μg、ANF/GAPDH(0.587±0.012)、β-MHC/GAPDH(0.422±0.016)、CaN/GAPDH(0.529±0.006)及NFAT3/Histone3(0.811±0.014)相比,给予TGR5受体激动剂组心肌细胞表面积(2 421.69±123.61)um~2、总蛋白(42.714±0.542)μg、ANF/GAPDH(0.229±0.011)、β-MHC/GAPDH(0.230±0.018)、CaN/GAPDH(0.247±0.008)及NFAT3/Histone3(0.407±0.008)的表达表达增加受到抑制(P<0.05)。予以siTGR5转染细胞后,部分消除了上述的抑制作用(P<0.05)。结论激活TGR5可改善ET-1诱导心肌细胞肥大,其机制可能部分与抑制CaN/NFAT3信号通路有关。
Objective To investigate the inhibitory effect of G protein-coupled bile acid receptor 1(TGR5) on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy and explore the mechanism. Methods Primary cultured neonatal rat cardiomyocytes were exposed to ET-1 at 10~(-6), 10~(-7), or 10~(-8) mmol/L for 12, 24, 36, or 48 h, and the surface area and total protein concentration of the cells were measured to verify the establishment of cardiac mast cell models. In the subsequent experiment, rat cardiomyocytes were treated with ET-1, ET-1+INT-777(a TGR5 receptor agonist), ET-1+INT-777+TGR5 siRNA, or ET-1+ INT-777+TGR5 siRNA-NC(an empty viral vector). The surface area of the cardiomyocytes was measured using an image analysis system, and the total protein content in the cells was determined with BCA method; The mRNA levels of TGR5 and calcineurin(CaN) were detected using RT-PCR, and the protein levels of atrial natriuretic factor(ANF), β-myosin heavy chain(β-MHC), TGR5, CaN and activated T cell nuclear factor 3(NFAT3) were determined using Western blotting. Results Within 48 h, ET-1 concentration-and time-dependently induced cardiomyocyte hypertrophy in the concentration range of 1×10~(-8) to 1×10~(-6) mmol/L(P<0.05). ET-1 treatment resulted in significantly increased surface area(3 624.7±71.60 μm~2) and total protein content(51.810±1.47 μg) in the cardiomyocytes at 48 h as compared with the those in the control cells(1 560.8±3 188.94 μm~2 and 37.827±0.47 μg, respectively; P<0.05). ET-1 exposure of the cells caused also significantly increased expression of ANF, β-MHC, CaN and NFAT3(P<0.05). Compared with the cells treated with ET-1 alone, the cells with both ET-1 and INT-777 treatment showed significantly reduced total cell surface area, total protein content, and protein expressions of ANF, β-MHC, CaN and NFAT3(P<0.05). Transfection with siTGR5 partially eliminated the inhibitory effects of INT-777 on ET-1-induced cardiomyocyte hypertrophy(P<0.05). Conclusion Activation of TGR5 may ameliorate ET-1-induced cardiomyocyte hypertrophy, the mechanism of which is related to the inhibition of CaN/NFAT3 signaling pathway.
Objective To investigate the inhibitory effect of G protein-coupled bile acid receptor 1(TGR5) on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy and explore the mechanism. Methods Primary cultured neonatal rat cardiomyocytes were exposed to ET-1 at 10~(-6), 10~(-7), or 10~(-8) mmol/L for 12, 24, 36, or 48 h, and the surface area and total protein concentration of the cells were measured to verify the establishment of cardiac mast cell models. In the subsequent experiment, rat cardiomyocytes were treated with ET-1, ET-1+INT-777(a TGR5 receptor agonist), ET-1+INT-777+TGR5 siRNA, or ET-1+ INT-777+TGR5 siRNA-NC(an empty viral vector). The surface area of the cardiomyocytes was measured using an image analysis system, and the total protein content in the cells was determined with BCA method; The mRNA levels of TGR5 and calcineurin(CaN) were detected using RT-PCR, and the protein levels of atrial natriuretic factor(ANF), β-myosin heavy chain(β-MHC), TGR5, CaN and activated T cell nuclear factor 3(NFAT3) were determined using Western blotting. Results Within 48 h, ET-1 concentration-and time-dependently induced cardiomyocyte hypertrophy in the concentration range of 1×10~(-8) to 1×10~(-6) mmol/L(P<0.05). ET-1 treatment resulted in significantly increased surface area(3 624.7±71.60 μm~2) and total protein content(51.810±1.47 μg) in the cardiomyocytes at 48 h as compared with the those in the control cells(1 560.8±3 188.94 μm~2 and 37.827±0.47 μg, respectively; P<0.05). ET-1 exposure of the cells caused also significantly increased expression of ANF, β-MHC, CaN and NFAT3(P<0.05). Compared with the cells treated with ET-1 alone, the cells with both ET-1 and INT-777 treatment showed significantly reduced total cell surface area, total protein content, and protein expressions of ANF, β-MHC, CaN and NFAT3(P<0.05). Transfection with siTGR5 partially eliminated the inhibitory effects of INT-777 on ET-1-induced cardiomyocyte hypertrophy(P<0.05). Conclusion Activation of TGR5 may ameliorate ET-1-induced cardiomyocyte hypertrophy, the mechanism of which is related to the inhibition of CaN/NFAT3 signaling pathway.
引文
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[2] FAGAN K A,MCMURTRY I F,RODMAN D M.Role of endothelin-1 in lung disease[J].Respir Res,2001,2(2):90.DOI:10.1186/rr44.
[3] WU W,KUANG P,LI Z.Changes of endothelin-1 gene expression in rat brains during ischemia and ischemic reperfusion[J].Chin Med Sci J,1996,11(4):228-231.
[4] KOHAN D E.The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure[J].Curr Opin Nephrol Hypertens,2006,15(1):34-40.
[5] 孔宏亮,黄带发,王聿杰,等.人参皂甙 Rbl 通过 PKC 途径抑制 ET-1诱发的乳鼠心肌肥大[J].心血管康复医学杂志,2015,24(1):10-15.DOI:10.3969/j.issn.1008-0074.2015.01.03.KONG H L,HUANG D F,WANG Y J,et al.Ginsenosides-Rbl inhibits ET-1-induced cardiomyocyte hypertrophy via PKC pathway in neonatal rats[J].Chin J Cardiovasc Rehabil Med,2015,24(1):10-15.DOI:10.3969/j.issn.1008-0074.2015.01.03.
[6] ICHIKAWA K I,HIDAI C,OKUDA C,et al.Endogenous endothelin-1 mediates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium[J].J Am Coll Cardiol,1996,27(5):1286-1291.DOI:10.1016/0735-1097(95)00568-4.
[7] LIOU S F,HSU J H,CHEN Y T,et al.KMUP-1 attenuates endothelin-1-induced cardiomyocyte hypertrophy through activation of heme oxygenase-1 and suppression of the Akt/GSK-3β,Calcineurin/NFATc4 and RhoA/ROCK pathways[J].Molecules,2015,20(6):10435-10449.DOI:10.3390/molecules200610435.
[8] KALK P,WESTERMANN D,HERZFELD S,et al.Additional lack of iNOS attenuates diastolic dysfunction in aged ET-1 transgenic mice[J].Can J Physiol Pharmacol,2008,86(6):353-357.DOI:10.1139/Y08-032.
[9] ARCHER C R,ROBINSON E L,DRAWNEL F M,et al.Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors[J].Cell Signal,2017,36:240-254.DOI:10.1016/j.cellsig.2017.04.010.
[10] KIRKBY S,HADOKE F,BAGNALL J,et al.The endothelin system as a therapeutic target in cardiovascular disease:great expectations or bleak house?[J].Br J Pharmacol,2009,153(6):1105-1119.DOI:10.1038/sj.bjp.0707516.
[11] KAWAMATA Y,FUJII R,HOSOYA M,et al.A G protein-coupled receptor responsive to bile acids[J].J Biol Chem,2003,278(11):9435-9440.DOI:10.1074/jbc.m209706200.
[12] POLS T W H,NORIEGA L G,NOMURA M,et al.The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation[J].J Hepatol,2011,54(6):1263-1272.DOI:10.1016/j.jhep.2010.12.004.
[13] 郝保兵,饶建华,吕凌,等.胆汁酸膜受体TGR5在肝脏代谢免疫中的研究进展[J].中华肝胆外科杂志,2014,20(11):834-837.HAO B B,RAO J H,LYU L,et al.Progress of TGR5 receptors in liver metabolism and immune [J].Chin J Hepatobil Surg,2014,20(11):834-837.
[14] 颜勇,李旭忠,王时光,等.G蛋白偶联胆汁酸受体TGR5在炎症及炎性疾病中的作用[J].医学研究杂志,2016,45(3):185-188.YAN Y,LI X Z,WANG S G,et al.The role of G-protein-conjugated bile acid receptor TGR5 in inflammation and inflammatory diseases [J].J Med Res,2016,45(3):185-188.
[15] 冯健,吴丹,陈旭昕,等.激活 TGR5通过 CaN/NFAT3途径减轻高糖诱导的心肌细胞肥大[J].中国病理生理杂志,2017,33(2):239-243.DOI:10.3969/j.issn.1000-4718.2017.02.008.FENG J,WU D,CHEN X X,et al.Activation of TGR5 reduces high glucose-induced cardiomyocyte hyper-trophy by inhibiting CaN/NFAT3 signaling[J].Chin J Pathophysiol,2017,33(2):239-243.DOI:10.3969/j.issn.1000-4718.2017.02.008.
[16] 吴丹,冯健,莫显刚,等.改良的乳小鼠心肌细胞原代培养方法[J].中国比较医学杂志,2016,26(4):62-67.WU D,FENG J,MO X G,et al.An improved method for primary culture of neonatal mouse cardiomyocytes [J].Chin J Comp med,2016,26(4):62-67.
[17] THAM Y K,BERNARDO B C,OOI J Y,et al.Pathophysiology of cardiac hypertrophy and heart failure:signaling pathways and novel therapeutic targets[J].Arch Toxicol,2015,89(9):1401-1438.DOI:10.1007/s00204-015-1477-x.
[18] 刘丽娜,李法琦.心肌肥厚相关信号通路的研究进展[J].重庆医学,2010,39(20):2805-2808 LIU L N,LI F Q.Advances in the study of signaling pathways related to cardiac hypertrophy [J].Chongqing Med,2010,39(20):2805-2808.
[19] HUNTER J J,CHIEN K R.Signaling pathways for cardiac hypertrophy and failure[J].N Engl J Med,1999,341(17):1276-1283.DOI:10.1056/nejm199910213411706.
[20] HONGO K,WHITE E,ORCHARD C H.Effect of stretch on contraction and the Ca2+ transient in ferret ventricular muscles during hypoxia and acidosis[J].Am J Physiol,1995,269(3 Pt 1):C690-C697.DOI:10.1152/ajpcell.1995.269.3.C690.
[21] 董化江,徐鹏霄.血管内皮素的研究进展[J].武警后勤学院学报(医学版),2009,18(6):557-560.DONG H J,XU P X.The research progress of endothelin axis [J].J Armed Police Logist Coll (Med Sci),2009,18(6):557-560.
[22] PERNOW J,SHEMYAKIN A,B?HM F.New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus[J].Life Sci,2012,1(13/14):507-516.DOI:10.1016/j.lfs.2012.03.029.
[23] SCHOOLING C M,KODALI H,LI S,et al.ET (endothelin)-1 and ischemic heart disease:A mendelian randomization study[J].Circ Genom Precis Med,2018,11(3):e002026.DOI:10.1161/CIRCGENETICS.117.002026.
[24] LI M,HE H P,GONG H Q,et al.NFATc4 and myocardin synergistically up-regulate the expression of LTCC α1C in ET-1-induced cardiomyocyte hypertrophy[J].Life Sci,2016,155:11-20.DOI:10.1016/j.lfs.2016.05.007.
[25] SUZUKI T,HOSHI H,MITSUI Y.Endothelin stimulates hypertrophy and contractility of neonatal rat cardiac myocytes in a serum-free medium[J].FEBS Lett,1990,268(1):149-151.
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