Elabela/APJ信号的结构与功能研究进展
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摘要
Elabelas/Toddlers是最近从斑马鱼中发现的一组内源性活性肽。研究发现该类肽基因序列与爱帕琳肽(Apelin)有25%的相似性,并且也通过血管紧张素Ⅱ1型受体相关蛋白(putative receptor protein related to the angio‐tensin receptor AT1, APJ)调控生物体内相应的生理功能,如早期胚胎发育、血管生成、体液平衡、摄食与饮食行为控制等;同时还参与多种疾病的发生发展过程,如心衰、先兆子痫、急性肾损伤、高血压和糖尿病等。近年来的研究表明, Elabela/APJ信号能促进生物体早期胚胎的正常发育,包括中内胚层、内胚层的分化以及心脏形态及功能的形成;同时该信号还能促进血管生成,从而促进肿瘤细胞的迁移和增殖。本文主要就Elabela/APJ信号的分子结构、生物学特性、功能及其应用前景进行阐述。
Elabelas/Toddlers belong to a group of endogenous active peptides recently discovered from zebrafish. The sequences of these peptides have 25% homology to Apelin. These peptides regulate physiological functions of organisms through putative protein receptors related to the angiotensin receptor AT1(APJ). Functional roles of Elabela include early embryonic development, angiogenesis, fluid homeostasis, and feeding or dietary behavior control. Elabela also participates in the development of many diseases, such as heart failure, preeclampsia,acute kidney injury, hypertension, and diabetes. Increasingly, studies have shown that Elabela/APJ signaling can promote normal development of early embryos, including differentiation of mesoderm and endoderm, and forma‐tion of cardiac morphology and function. At the same time, the signaling can also promote angiogenesis or migra‐tion and proliferation of tumor cells. Here we describe the molecular structure, biological characteristics, functions and application prospects of Elabela/APJ signaling.
Elabelas/Toddlers belong to a group of endogenous active peptides recently discovered from zebrafish. The sequences of these peptides have 25% homology to Apelin. These peptides regulate physiological functions of organisms through putative protein receptors related to the angiotensin receptor AT1(APJ). Functional roles of Elabela include early embryonic development, angiogenesis, fluid homeostasis, and feeding or dietary behavior control. Elabela also participates in the development of many diseases, such as heart failure, preeclampsia,acute kidney injury, hypertension, and diabetes. Increasingly, studies have shown that Elabela/APJ signaling can promote normal development of early embryos, including differentiation of mesoderm and endoderm, and forma‐tion of cardiac morphology and function. At the same time, the signaling can also promote angiogenesis or migra‐tion and proliferation of tumor cells. Here we describe the molecular structure, biological characteristics, functions and application prospects of Elabela/APJ signaling.
引文
[1]O'Dowd BF,Heiber M,Chan A,et al.A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11[J].Gene,1993,136:355-360.
[2]Tatemoto K,Hosoya M,Habata Y,et al.Isolation and character‐ization of a novel endogenous peptide ligand for the human APJreceptor[J].Biochem Biophys Res Commun,1998,251:471-476.
[3]Chng SC,Ho L,Tian J,et al.Elabela:a hormone essential for heart development signals via the Apelin receptor[J].Dev Cell,2013,27:672-680.
[4]Li LF,Zhou QL,Li XX,et al.Elabela-APJ axis:a novel therapy target for cardiovascular diseases[J].Acta Biochim Biophys Sin,2017,49:1042-1043.
[5]Artas G,Ozturk S,Kuloglu T,et al.A novel candidate molecule in the pathological grading of gliomas:Elabela[J].Turk Neuro‐surg,2018,28:989-994.
[6]Masri B,Knibiehler B,Audigier Y.Apelin signalling:a promising pathway from cloning to pharmacology[J].Cell Signal,2005,17:415-426.
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[8]Siddiquee K,Hampton J,Mc Anally D,et al.The Apelin receptor inhibits the angiontensin II type 1 receptor via allosteric transinhibition[J].Br J Pharmacol,2013,168:1104-1117.
[9]Wang Z,Yu D,Wang M,et al.Elabela-Apelin receptor signaling pathway is functional in mammalian systems[J].Sci Rep,2015,5:8170-8177.
[10]Murza A,Sainsily X,Coquerel D,et al.Discovery and structureactivity relationship of a bioactive fragment of Elabela that modulates vascular and cardiac functions[J].J Med Chem,2016,59:2962-2972.
[11]Ho L,Tan SY,Wee S,et al.Elabela is an endogenous growth factor that sustains hESC self-renewal via the PI3K/AKT pathway[J].Cell Stem Cell,2015,17:435-447.
[12]Tomimatsu T,Mimura K,Endo M,et al.Pathophysiology of preeclampsia:an angiogenic imbalance and long-lasting systemic vascular dysfunction[J].Hypertens Res,2017,40:305-310.
[13]Ho L,van Dijk M.Elabela deficiency promotes preeclampsia and cardiovascular malformations in mice[J].Science,2017,357:707-713.
[14]Panitescu B,Romero R,Gomez-Lopez N,et al.Elabela plasma concentrations are increased in women late-onset preeclampsia[J].J Matern Fetal Neonatal Med,2018,125:43-80.
[15]Lu L,Cao J,Li L,et al.Elabela,a new endogenous ligand of APJ,functions in embryos and adults organisms[J].Acta Biochim Biophys Sin,2017,49:378-381.
[16]Sato T,Sato C,Kadowaki A,et al.Elabela-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage[J].Cardiovasc Res,2017,113:760-769.
[17]Zhang D,Yang J.The current application of stem cell based therapy in pulmonary hypertension[J].Acta Pharm Sin(药学学报),2018,53:1778-1783.
[18]Yang P,Read C,Kuc RE,et al.Elabela/Toddler is an endogenous agonist of the Apelin APJ receptor in the adult cardiovascular system,and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension[J].Circulation,2017,135:1160-1173.
[19]Schreiber CA,Holditch SJ,Generous A,et al.Sustained Elabela gene therapy in high-salt diet-induced hypertensive rats[J].Curr Gene Ther,2017,16:349-360.
[20]Arai S,Kitada K,Yamazaki T,et al.Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice[J].Nat Med,2016,22:183-193.
[21]Rabb H,Griffin MD,McKay DB,et al.Inflammation in AKI:current understanding,key questions,and knowledge gaps[J].JAm Soc Nephrol,2016,27:371-379.
[22]Chen H,Wang L,Wang WJ,et al.Elabela and an Elabela fragment protect against AKI[J].J Am Soc Nephrol,2017,28:2694-2707.
[23]Zhou DD,Yu JJ,Hua F,et al.Macrophage migration inhibitory factor,a critical link between inflammation and cancer[J].Acta Pharm Sin(药学学报),2018,53:1761-1769.
[24]Holland EC.Glioblastoma multiforme:the terminator[J].Proc Natl Acad Sci U S A,2000,97:6242-6244.
[25]Hinrichs BH,Newman S,Appin CL,et al.Farewell to GBM-O:genomic and transcriptomic profling of glioblastoma with oligo‐dendroglioma component reveals distinct molecular subgroups[J].Acta Neuropathol Commun,2016,4:4-12.
[26]Liu Q,Hu T,He L,et al.Genetic targeting of sprouting angio‐genesis using AplnCreER[J].Nat Commun,2015,6020:7020-7031.
[27]Flyvbjerg A.The role of the complement system in diabetic nephropathy[J].Nat Rev Nephrol,2017,13:311-318.
[28]Wang L,Gao P,Zhang M,et al.Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013[J].JAMA,2017,317:2515-2523.
[29]Zhang H,Gong DW,Ni LQ,et al.Serum Elabela/Toddler levels are associated with albuminuria in patients with type 2 diabetes[J].Cell Physiol Biochem,2018,48:1347-1354.
[30]Huang Z,He L,Chen Z,et al.Targeting drugs to APJ receptor:from signaling to pathophysiological effects[J].J Cell Physiol,2018,234:61-74.
[2]Tatemoto K,Hosoya M,Habata Y,et al.Isolation and character‐ization of a novel endogenous peptide ligand for the human APJreceptor[J].Biochem Biophys Res Commun,1998,251:471-476.
[3]Chng SC,Ho L,Tian J,et al.Elabela:a hormone essential for heart development signals via the Apelin receptor[J].Dev Cell,2013,27:672-680.
[4]Li LF,Zhou QL,Li XX,et al.Elabela-APJ axis:a novel therapy target for cardiovascular diseases[J].Acta Biochim Biophys Sin,2017,49:1042-1043.
[5]Artas G,Ozturk S,Kuloglu T,et al.A novel candidate molecule in the pathological grading of gliomas:Elabela[J].Turk Neuro‐surg,2018,28:989-994.
[6]Masri B,Knibiehler B,Audigier Y.Apelin signalling:a promising pathway from cloning to pharmacology[J].Cell Signal,2005,17:415-426.
[7]Domazet I,Holleran BJ,Richard A,et al.Characterization of angiotensin II molecular determinants involved in AT1 receptor functional selectivity[J].Mol Pharmacol,2015,87:982-995.
[8]Siddiquee K,Hampton J,Mc Anally D,et al.The Apelin receptor inhibits the angiontensin II type 1 receptor via allosteric transinhibition[J].Br J Pharmacol,2013,168:1104-1117.
[9]Wang Z,Yu D,Wang M,et al.Elabela-Apelin receptor signaling pathway is functional in mammalian systems[J].Sci Rep,2015,5:8170-8177.
[10]Murza A,Sainsily X,Coquerel D,et al.Discovery and structureactivity relationship of a bioactive fragment of Elabela that modulates vascular and cardiac functions[J].J Med Chem,2016,59:2962-2972.
[11]Ho L,Tan SY,Wee S,et al.Elabela is an endogenous growth factor that sustains hESC self-renewal via the PI3K/AKT pathway[J].Cell Stem Cell,2015,17:435-447.
[12]Tomimatsu T,Mimura K,Endo M,et al.Pathophysiology of preeclampsia:an angiogenic imbalance and long-lasting systemic vascular dysfunction[J].Hypertens Res,2017,40:305-310.
[13]Ho L,van Dijk M.Elabela deficiency promotes preeclampsia and cardiovascular malformations in mice[J].Science,2017,357:707-713.
[14]Panitescu B,Romero R,Gomez-Lopez N,et al.Elabela plasma concentrations are increased in women late-onset preeclampsia[J].J Matern Fetal Neonatal Med,2018,125:43-80.
[15]Lu L,Cao J,Li L,et al.Elabela,a new endogenous ligand of APJ,functions in embryos and adults organisms[J].Acta Biochim Biophys Sin,2017,49:378-381.
[16]Sato T,Sato C,Kadowaki A,et al.Elabela-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage[J].Cardiovasc Res,2017,113:760-769.
[17]Zhang D,Yang J.The current application of stem cell based therapy in pulmonary hypertension[J].Acta Pharm Sin(药学学报),2018,53:1778-1783.
[18]Yang P,Read C,Kuc RE,et al.Elabela/Toddler is an endogenous agonist of the Apelin APJ receptor in the adult cardiovascular system,and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension[J].Circulation,2017,135:1160-1173.
[19]Schreiber CA,Holditch SJ,Generous A,et al.Sustained Elabela gene therapy in high-salt diet-induced hypertensive rats[J].Curr Gene Ther,2017,16:349-360.
[20]Arai S,Kitada K,Yamazaki T,et al.Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice[J].Nat Med,2016,22:183-193.
[21]Rabb H,Griffin MD,McKay DB,et al.Inflammation in AKI:current understanding,key questions,and knowledge gaps[J].JAm Soc Nephrol,2016,27:371-379.
[22]Chen H,Wang L,Wang WJ,et al.Elabela and an Elabela fragment protect against AKI[J].J Am Soc Nephrol,2017,28:2694-2707.
[23]Zhou DD,Yu JJ,Hua F,et al.Macrophage migration inhibitory factor,a critical link between inflammation and cancer[J].Acta Pharm Sin(药学学报),2018,53:1761-1769.
[24]Holland EC.Glioblastoma multiforme:the terminator[J].Proc Natl Acad Sci U S A,2000,97:6242-6244.
[25]Hinrichs BH,Newman S,Appin CL,et al.Farewell to GBM-O:genomic and transcriptomic profling of glioblastoma with oligo‐dendroglioma component reveals distinct molecular subgroups[J].Acta Neuropathol Commun,2016,4:4-12.
[26]Liu Q,Hu T,He L,et al.Genetic targeting of sprouting angio‐genesis using AplnCreER[J].Nat Commun,2015,6020:7020-7031.
[27]Flyvbjerg A.The role of the complement system in diabetic nephropathy[J].Nat Rev Nephrol,2017,13:311-318.
[28]Wang L,Gao P,Zhang M,et al.Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013[J].JAMA,2017,317:2515-2523.
[29]Zhang H,Gong DW,Ni LQ,et al.Serum Elabela/Toddler levels are associated with albuminuria in patients with type 2 diabetes[J].Cell Physiol Biochem,2018,48:1347-1354.
[30]Huang Z,He L,Chen Z,et al.Targeting drugs to APJ receptor:from signaling to pathophysiological effects[J].J Cell Physiol,2018,234:61-74.