Epac信号分子在心血管疾病中的研究进展
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摘要
3',5'-环磷酸腺苷(cAMP)直接激活交换蛋白(Epac)是小GTP酶Ras超家族Rap1和Rap2的鸟嘌呤核苷酸交换因子,参与细胞黏附、细胞间连接、胞吐/分泌、细胞增殖和分化等cAMP相关的细胞功能。近几年,许多外文文献报道了Epac在各种cAMP依赖性心血管疾病中的功能,如心肌肥大、纤维化、凋亡、心律失常和血管调节作用,而国内研究报道则较少。本文对Epac与心血管系统的作用及机制进行综述,以促进Epac相关药物的研究。
Epacs are GEFs( guanine-nucleotide-exchange factors) for the small Ras-like GTPases Rap1 and Rap2. Epac proteins play a key role in the host of cAMP-related cellular functions,such as cell adhesion,cell-cell junction,exocytosis/secretion,phagocytosis,cell proliferation and differentiation,gene expression,cardiac hypertrophy,apoptosis,and so on. In recent years,many foreign literatures reported Epacs involved in a variety of cAMP-dependent cardiovascular diseases,such as cardiac hypertrophy,cardiac fibrosis,apoptosis,arrhythmia and vasculature regulation,while domestic research reports are quite few. In this paper,we reviewed the effects of Epacs on the cardiovascular diseases,andon the regulation mechanism of cardiac apoptosis and hypertrophy,to facilitate the study on the Epacs related drugs.
Epacs are GEFs( guanine-nucleotide-exchange factors) for the small Ras-like GTPases Rap1 and Rap2. Epac proteins play a key role in the host of cAMP-related cellular functions,such as cell adhesion,cell-cell junction,exocytosis/secretion,phagocytosis,cell proliferation and differentiation,gene expression,cardiac hypertrophy,apoptosis,and so on. In recent years,many foreign literatures reported Epacs involved in a variety of cAMP-dependent cardiovascular diseases,such as cardiac hypertrophy,cardiac fibrosis,apoptosis,arrhythmia and vasculature regulation,while domestic research reports are quite few. In this paper,we reviewed the effects of Epacs on the cardiovascular diseases,andon the regulation mechanism of cardiac apoptosis and hypertrophy,to facilitate the study on the Epacs related drugs.
引文
[1]SUGAWARA K,SHIBASAKI T,TAKAHASHI H,et al.Structure and functional roles of Epac2(Rapgef4)[J].Gene,2016,575(2 Pt 3):577-583.
[2]CHEN H,WILD C,ZHOU X,et al.Recent advances in the discovery of small molecules targeting exchange proteins directly activated by c AMP(EPAC)[J].J Med Chem,2014,57(9):3651-3665.
[3]METRICH M,BERTHOUZE M,MOREL E,et al.Role of the c AMP-binding protein Epac in cardiovascular physiology and pathophysiology[J].Pflugers Arch,2010,459(4):535-546.
[4]PARNELL E,SMITH BO,YARWOOD SJ.The c AMP sensors,EPAC1 and EPAC2,display distinct subcellular distributions despite sharing a common nuclear pore localisation signal[J].Cell Signal,2015,27(5):989-996.
[5]PEREIRA L,REHMANN H,LAO DH,et al.Novel Epac fluorescent ligand reveals distinct Epac1 vs.Epac2 distribution and function in cardiomyocytes[J].Proc Natl Acad Sci USA,2015,112(13):3991-3996.
[6]LAURENT AC,BISSERIER M,LUCAS A,et al.Exchange protein directly activated by c AMP 1 promotes autophagy during cardiomyocyte hypertrophy[J].Cardiovasc Res,2015,105(1):55-64.
[7]CHENG X,JI Z,TSALKOVA T,et al.Epac and PKA:a tale of two intracellular c AMP receptors[J].Acta Biochim Biophys Sin(Shanghai),2008,40(7):651-662.
[8]SCOTT J,HARRIS GJ,PINDER EM,et al.Exchange protein directly activated by cyclic AMP(EPAC)activation reverses neutrophil dysfunction induced by beta2-agonists,corticosteroids,and critical illness[J].J Allergy Clin Immunol,2016,137(2):535-544.
[9]BIRUKOVA AA,MENG F,TIAN Y,et al.Prostacyclin posttreatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1[J].Biochim Biophys Acta,2015,1852(5):778-791.
[10]孙月.Ac-SDKP活化c AMP/Epac信号转导通路对AngⅡ介导的矽肺肌成纤维细胞分化的调节[D].唐山:河北联合大学,2014.
[11]PEACE AG,SHEWAN DA.New perspectives in cyclic AMP-mediated axon growth and guidance:the emerging epoch of Epac[J].Brain Res Bull,2011,84(4-5):280-288.
[12]吴园园,李涵,杨萍.c AMP促进成年哺乳动物中枢神经系统再生分子机制的研究进展[J].国际神经病学神经外科学杂志,2010,37(1):88-91.
[13]张涛,文益民,魏祥科,等.c AMP衍生物特异性激活Epac2/Akt信号通路促进大鼠脊髓损伤的修复[J].第三军医大学学报,2012,34(24):2493-2497.
[14]OLDENBURGER A,ROSCIONI SS,JANSEN E,et al.Anti-inflammatory role of the c AMP effectors Epac and PKA:implications in chronic obstructive pulmonary disease[J].PLo S One,2012,7(2):e31574.
[15]SINGHMAR P,HUO X,EIJKELKAMP N,et al.Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1[J].Proc Natl Acad Sci USA,2016,113(11):3036-3041.
[16]李琳.β肾上腺素能受体活化蛋白激酶C_ε诱导心肌细胞肥大及其机制探讨[D].昆明:昆明医科大学,2011.
[17]李琳,蔡红雁,郭涛.β肾上腺素能受体活化蛋白激酶C诱导心肌细胞肥大[J].中华高血压杂志,2010,18(2):165-170.
[18]李琳,郭涛.β肾上腺素能受体信号转导通路对心肌肥大的调节[J].心血管病学进展,2014,35(3):339-342.
[19]LI L,CAI H,LIU H,et al.Beta-adrenergic stimulation activates protein kinase Cepsilon and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy[J].Mol Med Rep,2015,11(6):4373-4380.
[20]METRICH M,LUCAS A,GASTINEAU M,et al.Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy[J].Circ Res,2008,102(8):959-965.
[21]METRICH M,LAURENT AC,BRECKLER M,et al.Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway[J].Cell Signal,2010,22(10):1459-1468.
[22]PEREIRA L,RUIZ-HURTADO G,MOREL E,et al.Epac enhances excitation-transcription coupling in cardiac myocytes[J].J Mol Cell Cardiol,2012,52(1):283-291.
[23]MONCEAU V,LLACH A,AZRIA D,et al.Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis[J].Radiother Oncol,2014,111(1):63-71.
[24]OKUMURA S,FUJITA T,CAI W,et al.Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses[J].J Clin Invest,2014,124(6):2785-2801.
[25]INSEL PA,MURRAY F,YOKOYAMA U,et al.c AMP and Epac in the regulation of tissue fibrosis[J].Br J Pharmacol,2012,166(2):447-456.
[26]OLMEDO I,MUNOZ C,GUZMAN N,et al.EPAC expression and function in cardiac fibroblasts and myofibroblasts[J].Toxicol Appl Pharmacol,2013,272(2):414-422.
[27]MILLER CL,CAI Y,OIKAWA M,et al.Cyclic nucleotide phosphodiesterase 1A:a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart[J].Basic Res Cardiol,2011,106(6):1023-1039.
[28]CAI W,FUJITA T,HIDAKA Y,et al.Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction[J].Biochem Biophys Res Commun,2016,475(1):1-7.
[29]INSEL PA,ZHANG L,MURRAY F,et al.Cyclic AMP is botha pro-apoptotic and anti-apoptotic second messenger[J].Acta Physiol(Oxf),2012,204(2):277-287.
[30]ZHANG X,SZETO C,GAO E,et al.Cardiotoxic and cardioprotective features of chronic beta-adrenergic signaling[J].Circ Res,2013,112(3):498-509.
[31]AOYAMA M,KAWASE H,BANDO YK,et al.Dipeptidyl Peptidase 4 inhibition alleviates shortage of circulating glucagon-like Peptide-1 in heart failure and mitigates myocardial remodeling and apoptosis via the exchange protein directly activated by cyclic AMP 1/ras-related protein 1 axis[J].Circ Heart Fail,2016,9(1):e002081.
[32]WU XM,OU QY,ZHAO W,et al.The GLP-1 analogue liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway[J].Exp Clin Endocrinol Diabetes,2014,122(10):608-614.
[33]MANGMOOL S,HEMPLUEKSA P,PARICHATIKANOND W,et al.Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes[J].Mol Endocrinol,2015,29(4):583-596.
[34]LEZOUALC'H F,FAZAL L,LAUDETTE M,et al.Cyclic AMP sensor EPAC proteins and their role in cardiovascular function and disease[J].Circ Res,2016,118(5):881-897.
[35]PEREIRA L,CHENG H,LAO DH,et al.Epac2 mediates cardiac beta1-adrenergic-dependent sarcoplasmic reticulum Ca2+leak and arrhythmia[J].Circulation,2013,127(8):913-922.
[36]AFLAKI M,QI XY,XIAO L,et al.Exchange protein directly activated by c AMP mediates slow delayed-rectifier current remodeling by sustained beta-adrenergic activation in guinea pig hearts[J].Circ Res,2014,114(6):993-1003.
[37]BOBIN P,VARIN A,LEFEBVRE F,et al.Calmodulin kinase II inhibition limits the pro-arrhythmic Ca2+waves induced by c AMP-phosphodiesterase inhibitors[J].Cardiovasc Res,2016,110(1):151-161.
[38]RUIZ-HURTADO G,DOMINGUEZ-RODRIGUEZ A,PEREIRA L,et al.Sustained Epac activation induces calmodulin dependent positive inotropic effect in adult cardiomyocytes[J].J Mol Cell Cardiol,2012,53(5):617-625.
[39]DOMINGUEZ-RODRIGUEZ A,RUIZ-HURTADO G,SABOURIN J,et al.Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes[J].J Mol Cell Cardiol,2015,87:74-78.
[40]PARNELL E,PALMER TM,YARWOOD SJ.The future of EPAC-targeted therapies:agonism versus antagonism[J].Trends Pharmacol Sci,2015,36(4):203-214.
[41]ROBERTS OL,DART C.c AMP signalling in the vasculature:the role of Epac(exchange protein directly activated by c AMP)[J].Biochem Soc Trans,2014,42(1):89-97.
[42]PARNELL E,YARWOOD SJ.Interactions between Epac1 and ezrin in the control of endothelial barrier function[J].Biochem Soc Trans,2014,42(2):274-278.
[43]KIMURA TE,DUGGIRALA A,HINDMARCH CC,et al.Inhibition of Egr1 expression underlies the anti-mitogenic effects of c AMP in vascular smooth muscle cells[J].J Mol Cell Cardiol,2014,72:9-19.
[44]HEWER RC,SALA-NEWBY GB,WU YJ,et al.PKA and Epac synergistically inhibit smooth muscle cell proliferation[J].J Mol Cell Cardiol,2011,50(1):87-98.
[45]LEHRKE M,KAHLES F,MAKOWSKA A,et al.PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner[J].J Mol Cell Cardiol,2015,81:23-33.
[46]MCKEAN JS,MURRAY F,GIBSON G,et al.The c AMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by c AMP[J].Cardiovasc Res,2015,107(4):546-555.
[47]KATO Y,YOKOYAMA U,YANAI C,et al.Epac1 deficiency attenuated vascular smooth muscle cell migration and neointimal formation[J].Arterioscler Thromb Vasc Biol,2015,35(12):2617-2625.
[48]POST A,PANNEKOEK WJ,ROSS SH,et al.Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through Arh GAP29[J].Proc Natl Acad Sci USA,2013,110(28):11427-11432.
[49]SCHLEGEL N,WASCHKE J.c AMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier-a signaling pathway compromised in inflammation[J].Cell Tissue Res,2014,355(3):587-596.
[50]ZIEBA BJ,ARTAMONOV MV,JIN L,et al.The c AMP-responsive Rap1 guanine nucleotide exchange factor,Epac,induces smooth muscle relaxation by down-regulation of Rho A activity[J].J Biol Chem,2011,286(19):16681-16692.
[51]LAKSHMIKANTHAN S,ZIEBA BJ,GE ZD,et al.Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure[J].Arterioscler Thromb Vasc Biol,2014,34(7):1486-1494.
[2]CHEN H,WILD C,ZHOU X,et al.Recent advances in the discovery of small molecules targeting exchange proteins directly activated by c AMP(EPAC)[J].J Med Chem,2014,57(9):3651-3665.
[3]METRICH M,BERTHOUZE M,MOREL E,et al.Role of the c AMP-binding protein Epac in cardiovascular physiology and pathophysiology[J].Pflugers Arch,2010,459(4):535-546.
[4]PARNELL E,SMITH BO,YARWOOD SJ.The c AMP sensors,EPAC1 and EPAC2,display distinct subcellular distributions despite sharing a common nuclear pore localisation signal[J].Cell Signal,2015,27(5):989-996.
[5]PEREIRA L,REHMANN H,LAO DH,et al.Novel Epac fluorescent ligand reveals distinct Epac1 vs.Epac2 distribution and function in cardiomyocytes[J].Proc Natl Acad Sci USA,2015,112(13):3991-3996.
[6]LAURENT AC,BISSERIER M,LUCAS A,et al.Exchange protein directly activated by c AMP 1 promotes autophagy during cardiomyocyte hypertrophy[J].Cardiovasc Res,2015,105(1):55-64.
[7]CHENG X,JI Z,TSALKOVA T,et al.Epac and PKA:a tale of two intracellular c AMP receptors[J].Acta Biochim Biophys Sin(Shanghai),2008,40(7):651-662.
[8]SCOTT J,HARRIS GJ,PINDER EM,et al.Exchange protein directly activated by cyclic AMP(EPAC)activation reverses neutrophil dysfunction induced by beta2-agonists,corticosteroids,and critical illness[J].J Allergy Clin Immunol,2016,137(2):535-544.
[9]BIRUKOVA AA,MENG F,TIAN Y,et al.Prostacyclin posttreatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1[J].Biochim Biophys Acta,2015,1852(5):778-791.
[10]孙月.Ac-SDKP活化c AMP/Epac信号转导通路对AngⅡ介导的矽肺肌成纤维细胞分化的调节[D].唐山:河北联合大学,2014.
[11]PEACE AG,SHEWAN DA.New perspectives in cyclic AMP-mediated axon growth and guidance:the emerging epoch of Epac[J].Brain Res Bull,2011,84(4-5):280-288.
[12]吴园园,李涵,杨萍.c AMP促进成年哺乳动物中枢神经系统再生分子机制的研究进展[J].国际神经病学神经外科学杂志,2010,37(1):88-91.
[13]张涛,文益民,魏祥科,等.c AMP衍生物特异性激活Epac2/Akt信号通路促进大鼠脊髓损伤的修复[J].第三军医大学学报,2012,34(24):2493-2497.
[14]OLDENBURGER A,ROSCIONI SS,JANSEN E,et al.Anti-inflammatory role of the c AMP effectors Epac and PKA:implications in chronic obstructive pulmonary disease[J].PLo S One,2012,7(2):e31574.
[15]SINGHMAR P,HUO X,EIJKELKAMP N,et al.Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1[J].Proc Natl Acad Sci USA,2016,113(11):3036-3041.
[16]李琳.β肾上腺素能受体活化蛋白激酶C_ε诱导心肌细胞肥大及其机制探讨[D].昆明:昆明医科大学,2011.
[17]李琳,蔡红雁,郭涛.β肾上腺素能受体活化蛋白激酶C诱导心肌细胞肥大[J].中华高血压杂志,2010,18(2):165-170.
[18]李琳,郭涛.β肾上腺素能受体信号转导通路对心肌肥大的调节[J].心血管病学进展,2014,35(3):339-342.
[19]LI L,CAI H,LIU H,et al.Beta-adrenergic stimulation activates protein kinase Cepsilon and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy[J].Mol Med Rep,2015,11(6):4373-4380.
[20]METRICH M,LUCAS A,GASTINEAU M,et al.Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy[J].Circ Res,2008,102(8):959-965.
[21]METRICH M,LAURENT AC,BRECKLER M,et al.Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway[J].Cell Signal,2010,22(10):1459-1468.
[22]PEREIRA L,RUIZ-HURTADO G,MOREL E,et al.Epac enhances excitation-transcription coupling in cardiac myocytes[J].J Mol Cell Cardiol,2012,52(1):283-291.
[23]MONCEAU V,LLACH A,AZRIA D,et al.Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis[J].Radiother Oncol,2014,111(1):63-71.
[24]OKUMURA S,FUJITA T,CAI W,et al.Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses[J].J Clin Invest,2014,124(6):2785-2801.
[25]INSEL PA,MURRAY F,YOKOYAMA U,et al.c AMP and Epac in the regulation of tissue fibrosis[J].Br J Pharmacol,2012,166(2):447-456.
[26]OLMEDO I,MUNOZ C,GUZMAN N,et al.EPAC expression and function in cardiac fibroblasts and myofibroblasts[J].Toxicol Appl Pharmacol,2013,272(2):414-422.
[27]MILLER CL,CAI Y,OIKAWA M,et al.Cyclic nucleotide phosphodiesterase 1A:a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart[J].Basic Res Cardiol,2011,106(6):1023-1039.
[28]CAI W,FUJITA T,HIDAKA Y,et al.Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction[J].Biochem Biophys Res Commun,2016,475(1):1-7.
[29]INSEL PA,ZHANG L,MURRAY F,et al.Cyclic AMP is botha pro-apoptotic and anti-apoptotic second messenger[J].Acta Physiol(Oxf),2012,204(2):277-287.
[30]ZHANG X,SZETO C,GAO E,et al.Cardiotoxic and cardioprotective features of chronic beta-adrenergic signaling[J].Circ Res,2013,112(3):498-509.
[31]AOYAMA M,KAWASE H,BANDO YK,et al.Dipeptidyl Peptidase 4 inhibition alleviates shortage of circulating glucagon-like Peptide-1 in heart failure and mitigates myocardial remodeling and apoptosis via the exchange protein directly activated by cyclic AMP 1/ras-related protein 1 axis[J].Circ Heart Fail,2016,9(1):e002081.
[32]WU XM,OU QY,ZHAO W,et al.The GLP-1 analogue liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway[J].Exp Clin Endocrinol Diabetes,2014,122(10):608-614.
[33]MANGMOOL S,HEMPLUEKSA P,PARICHATIKANOND W,et al.Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes[J].Mol Endocrinol,2015,29(4):583-596.
[34]LEZOUALC'H F,FAZAL L,LAUDETTE M,et al.Cyclic AMP sensor EPAC proteins and their role in cardiovascular function and disease[J].Circ Res,2016,118(5):881-897.
[35]PEREIRA L,CHENG H,LAO DH,et al.Epac2 mediates cardiac beta1-adrenergic-dependent sarcoplasmic reticulum Ca2+leak and arrhythmia[J].Circulation,2013,127(8):913-922.
[36]AFLAKI M,QI XY,XIAO L,et al.Exchange protein directly activated by c AMP mediates slow delayed-rectifier current remodeling by sustained beta-adrenergic activation in guinea pig hearts[J].Circ Res,2014,114(6):993-1003.
[37]BOBIN P,VARIN A,LEFEBVRE F,et al.Calmodulin kinase II inhibition limits the pro-arrhythmic Ca2+waves induced by c AMP-phosphodiesterase inhibitors[J].Cardiovasc Res,2016,110(1):151-161.
[38]RUIZ-HURTADO G,DOMINGUEZ-RODRIGUEZ A,PEREIRA L,et al.Sustained Epac activation induces calmodulin dependent positive inotropic effect in adult cardiomyocytes[J].J Mol Cell Cardiol,2012,53(5):617-625.
[39]DOMINGUEZ-RODRIGUEZ A,RUIZ-HURTADO G,SABOURIN J,et al.Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes[J].J Mol Cell Cardiol,2015,87:74-78.
[40]PARNELL E,PALMER TM,YARWOOD SJ.The future of EPAC-targeted therapies:agonism versus antagonism[J].Trends Pharmacol Sci,2015,36(4):203-214.
[41]ROBERTS OL,DART C.c AMP signalling in the vasculature:the role of Epac(exchange protein directly activated by c AMP)[J].Biochem Soc Trans,2014,42(1):89-97.
[42]PARNELL E,YARWOOD SJ.Interactions between Epac1 and ezrin in the control of endothelial barrier function[J].Biochem Soc Trans,2014,42(2):274-278.
[43]KIMURA TE,DUGGIRALA A,HINDMARCH CC,et al.Inhibition of Egr1 expression underlies the anti-mitogenic effects of c AMP in vascular smooth muscle cells[J].J Mol Cell Cardiol,2014,72:9-19.
[44]HEWER RC,SALA-NEWBY GB,WU YJ,et al.PKA and Epac synergistically inhibit smooth muscle cell proliferation[J].J Mol Cell Cardiol,2011,50(1):87-98.
[45]LEHRKE M,KAHLES F,MAKOWSKA A,et al.PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner[J].J Mol Cell Cardiol,2015,81:23-33.
[46]MCKEAN JS,MURRAY F,GIBSON G,et al.The c AMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by c AMP[J].Cardiovasc Res,2015,107(4):546-555.
[47]KATO Y,YOKOYAMA U,YANAI C,et al.Epac1 deficiency attenuated vascular smooth muscle cell migration and neointimal formation[J].Arterioscler Thromb Vasc Biol,2015,35(12):2617-2625.
[48]POST A,PANNEKOEK WJ,ROSS SH,et al.Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through Arh GAP29[J].Proc Natl Acad Sci USA,2013,110(28):11427-11432.
[49]SCHLEGEL N,WASCHKE J.c AMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier-a signaling pathway compromised in inflammation[J].Cell Tissue Res,2014,355(3):587-596.
[50]ZIEBA BJ,ARTAMONOV MV,JIN L,et al.The c AMP-responsive Rap1 guanine nucleotide exchange factor,Epac,induces smooth muscle relaxation by down-regulation of Rho A activity[J].J Biol Chem,2011,286(19):16681-16692.
[51]LAKSHMIKANTHAN S,ZIEBA BJ,GE ZD,et al.Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure[J].Arterioscler Thromb Vasc Biol,2014,34(7):1486-1494.