自发性高血压大鼠不同G蛋白信号调节因子的变化Changes of different regulators of G protein signaling in spontaneously hypertensive rat
王玉艳,苏加林,毛源杰,薛林,赵春玉,宋以信,霍勇
摘要(Abstract)：
目的通过检测自发性高血压大鼠(spontaneously hypertensive rats,SHR)不同组织G蛋白信号调节因子(regulator of G protein signaling,RGS)包括RGS2、RGS3和RGS4 mRNA的变化及其与心血管系统生理学表型的相关性,探讨其在高血压中的作用及机制。方法SHR与正常血压对照组Wistar大鼠经颈动脉插管测量血流动力学指标,同时测定心重指数(heart weight/body mass,HW/BM)和左室质量指数(left ventricular mass index,LVMI)。提取主动脉和心肌组织总RNA,逆转录后采用实时定量聚合酶链式反应方法检测RGS2、RGS3和RGS4 mRNA水平。结果SHR组收缩压(229.2±30.6mm Hg比121.2±12.8mm Hg,P<0.01),HW/BM(0.34±0.01比0.26±0.01,P<0.01)和LVMI(0.28±0.01比0.21±0.01,P<0.01)均显著高于对照组。SHR组RGS2 mRNA水平与对照组相比,在主动脉中降低41.5%(0.69±0.14比1.18±0.26,P<0.05),心肌中升高3.3倍(0.20±0.04比0.06±0.01,P<0.05);SHR组主动脉和心肌中RGS3 mRNA水平分别较对照组升高4.2倍(1.51±0.20比0.36±0.06,P<0.01)和4.6倍(3.16±0.36比0.68±0.09,P<0.05)。SHR与对照组主动脉和心肌RGS4 mRNA水平差异无统计学意义。大鼠主动脉RGS2 mRNA水平与收缩压呈负相关(Y=-0.003X+0.89,P<0.05);心肌RGS2 mRNA水平与HW/BM(Y=1.56X-0.35,P<0.05)呈正相关。大鼠主动脉和心肌组织RGS3 mRNA水平呈正相关(P<0.05),并分别与收缩压(Y=0.01X-0.65,P<0.05)和LVM I(Y=23.8X-4.2,P<0.05)呈正相关。结论SHR大鼠主动脉选择性RGS2降低和RGS3升高可能参与了SHR高血压的发病,心脏RGS2和RGS3 mRNA水平升高与心肌肥厚和心脏收缩功能改变相关,提示RGS2和RGS3可能成为高血压及其心脏并发症药物治疗的新靶点。
关键词(KeyWords)： 高血压;GTP结合蛋白质调节剂;大鼠,近交SHR
基金项目(Foundation):
作者(Author): 王玉艳,苏加林,毛源杰,薛林,赵春玉,宋以信,霍勇
参考文献(References)：
- [1]Feldman RD,Gros R.Defective vasodilatory mechanisms in hy-pertension:a G-protein-coupled receptor perspective.Curr Opin Nephrol Hypertens,2006,15:135-140.
- [2]Foord SM,Bonner TI,Neubig RR,et al.G protein-coupled re-ceptor list.Pharmacol Rev,2005,57:279-288.
- [3]Dohlman HG,Song J,Ma D,et al.Sst2,a negative regulator of pheromone signaling in the yeast Saccharomyces cerevisiae:ex-pression,localization,and genetic interaction and physical asso-ciation with Gpa1(the G-protein alpha subunit).Mol Cell Biol,1996,16:5194-5209.
- [4]Ross EM,Wilkie TM.GTPase-activating proteins for heterotrim-eric G-proteins:regulators of G-protein signaling(RGS)and RGS-like proteins.Annu Rev Biochem,2000,69:795-827.
- [5]杨进华,郭志军.心肌组织中G蛋白信号转导调节蛋白研究进展.医学综述,2006,12:730-732.
- [6]Heximer SP,Knutsen RH,Sun X,et al.Hypertension and pro-longed vasoconstrictor signaling in RGS2-deficient mice.J Clin Invest,2003,111:445-452.
- [7]毛源杰,王玉艳,薛林,等.G蛋白信号调节因子2在血管重塑中的作用.中华医学杂志.2006,86(增刊2):334.
- [8]Heximer SP,Watson N,Linder ME,et al.RGS2/G0S8is a se-lective inhibitor of Gqalpha function.PNAS,1997,94:14389-14393.
- [9]Yang J,Kamide K,Kokubo Y,et al.Genetic variations of regu-lator of G-protein signaling2in hypertensive patients and in the general population.Hypertension,2005,23:1497-1505.
- [10]Calo LA,Pagnin E,Davis PA,et al.Increased Expression of Regulator of G Protein Signaling-2(RGS2)inBartter/Gitelman Syndrome.A Role in the Control of Vascular Tone and Implication for Hypertension.J Clin Endocrinol Metab,2004,89:4153-4157.
- [11]Semplicini A,Lenzini L,Sartori M,et al.Reduced expression of regulator of G-protein.signaling2(RGS2)in hypertensive pa-tients increases calcium mobilization and ERK1/2phosphoryla-tion induced by angiotensin II.J Hypertens,2006,24:1115-1124.
- [12]Zhang W,Anger T,Su J,et al.Selective Loss of Fine Tuning of Gq/11Signaling by RGS2Protein Exacerbates Cardiomyocyte Hypertrophy.J Biol Chem,2006,281:5811-5820.
- [13]Wang Q,Liu M,Mullah B,et al.Receptor-selective Effects of Endogenous RGS3and RGS5to Regulate Mitogen-activated Pro-tein Kinase Activation in Rat Vascular Smooth Muscle Cells.J Biol Chem,2002,277:24949-24958.
- [14]Zhang S,Watson N,Zahner J,at al.RGS3and RGS4are G protein inhibitors in the heart.J Mol Cell Cardiol,1998,30:269-276.
- [15]Dulin NO,Sorokin A,Reed E,et al.RGS3Inhibits G Protein-Mediated Signaling via Translocation to the Membrane and Bind-ing to Gα11.Mol Cell Biol,1999,19:714-723.
- [16]Berman DM,Wilkie TM,Gilman AG.GAIP and RGS4are GT-Pase-activating proteins for the Gi subfamily of G protein a sub-units.Cell,1996,86:445-452.
- [17]Hepler JR,Berman DM,Gilman AG,et al.RGS4and GAIP are GTPase-activating proteins for Gqa and block activation of phos-pholipase Cβby g-thio-GTP-Gqa.Proc Natl Acad Sci U S A,1997,94:428-432.
- [18]Tamirisa P,Blumer KJ,Muslin AJ.RGS4inhibits G-protein sig-naling in cardiomyocytes.Circulation,1999,99:441-447.