胰高血糖素样肽1(GLP-1)对心血管疾病治疗的研究进展
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摘要
胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)是肠道L细胞分泌的一种由30个氨基酸组成的多肽,具有促进胰岛素分泌,抑制胰高血糖素分泌和刺激胰岛β细胞增殖等生物学作用。GLP-1在体内主要以GLP-1(7-36a)的形式存在。GLP-1(7-36a)的半衰期很短(1～2 min),可被二肽基肽酶4(diaminopeptidyl peptidase-4,DPP4)迅速降解为GLP-1(9-36a),因此GLP-1(9-36a)是GLP-1在循环中的主要存在形式。GLP-1不仅具有调控血糖和能量代谢的作用,还有保护心肌细胞、改善心脏功能和舒张血管等作用,直接或间接发挥心血管保护效应。心血管疾病是2型糖尿病的常见并发症和首要死因。目前基于GLP-1的2型糖尿病药物研发主要有两个方向:可以抵抗DPP4降解的GLP-1受体(GLP-1R)激动剂和DPP4抑制剂。虽然,这两种方法均可延长内源性GLP-1的作用,但显然未兼顾GLP-1(9-36a)对心脏的保护效应。本文通过总结GLP-1(7-36a)及GLP-1(9-36a)在心血管效应方面的异同及其生理学研究进展,探讨GLP-1应用于心血管疾病治疗的新策略。
Glucagon-like peptide-1(GLP-1)is a 30-amino acid peptide hormone produced by intestinal L cells in response to food consumption.GLP-1(7-37)or GLP-1 amide(7-36 a)exerts insulinotropic effects including stimulating insulin secretion,suppressing glucagon release and promoting pancreaticβ-cell proliferation.The half-life of native 7-36 a is very short(1-2 min)due to the degrading emzyme diaminopeptidyl peptidase-4(DPP4)that cleaves 7-36 a at position 2 alanine to form GLP-1(9-36 a),which is the major circulating form.In addition to its glucose and energy regulatory effects,7-36 a and its metabolites 9-36 a have direct cardiovascular effects,including preserving cardiomyocyte viability and improving cardiac function.Cardiovascular disease is a common co-morbidity and leading cause of death in type 2 diabetes mellitus.Currently,there are two GLP-1 based therapies:development of DPP4-resistant GLP-1 receptor(GLP-1 R)agonists and DPP4 inhibitors.The two therapeutic strategies are all aimed at prolonging endogenous GLP-1 actions,while,lack of the cardiovascular benefits induced by 9-36 a.This work reviewed the advance in GLP-1 biology and attempted to distinguish the cardiovascular effects between7-36 a and9-36 a,aiming to provide new insights for the development of new strategy for GLP-1 therapies for the treatment of cardiovascular diseases.
Glucagon-like peptide-1(GLP-1)is a 30-amino acid peptide hormone produced by intestinal L cells in response to food consumption.GLP-1(7-37)or GLP-1 amide(7-36 a)exerts insulinotropic effects including stimulating insulin secretion,suppressing glucagon release and promoting pancreaticβ-cell proliferation.The half-life of native 7-36 a is very short(1-2 min)due to the degrading emzyme diaminopeptidyl peptidase-4(DPP4)that cleaves 7-36 a at position 2 alanine to form GLP-1(9-36 a),which is the major circulating form.In addition to its glucose and energy regulatory effects,7-36 a and its metabolites 9-36 a have direct cardiovascular effects,including preserving cardiomyocyte viability and improving cardiac function.Cardiovascular disease is a common co-morbidity and leading cause of death in type 2 diabetes mellitus.Currently,there are two GLP-1 based therapies:development of DPP4-resistant GLP-1 receptor(GLP-1 R)agonists and DPP4 inhibitors.The two therapeutic strategies are all aimed at prolonging endogenous GLP-1 actions,while,lack of the cardiovascular benefits induced by 9-36 a.This work reviewed the advance in GLP-1 biology and attempted to distinguish the cardiovascular effects between7-36 a and9-36 a,aiming to provide new insights for the development of new strategy for GLP-1 therapies for the treatment of cardiovascular diseases.
引文
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[9] KIRKPATRICK A,HEO J,ABROL R,et al.Predicted structure of agonist-bound glucagon-like peptide 1receptor,a class B G protein-coupled receptor[J].Proc Natl Acad Sci U S A,2012,109(49):19988-19993.
[10] KIM M,PLATT MJ,SHIBASAKI T,et al.GLP-1receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure[J].Nat Med,2013,19(5):567-575.
[11] PYKE C,HELLER RS,KIRK RK,et al.GLP-1 receptor localization inmonkeyandhumantissue:novel distributionrevealedwithextensivelyvalidated monoclonal antibody[J].Endocrinology,2014,155(4):1280-1290.
[12] PYKE C,KNUDSEN LB.The glucagon-like peptide-1receptor--or not?[J].Endocrinology,2013,154(1):4-8.
[13] LONBORG J,VEJLSTRUP N,KELBAEK H,et al.Exenatide reduces reperfusion injury in patients with STsegment elevation myocardial infarction[J].Eur Heart J,2012,33(12):1491-1499.
[14] WOHLFART P,LINZ W,HUBSCHLE T,et al.Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies[J].J Transl Med,2013,11:84.
[15] ARAVINDHAN K,BAO W,HARPEL MR,et al.Cardioprotection resulting from glucagon-like peptide-1administration involves shifting metabolic substrate utilization to increase energy efficiency in the rat heart[J].PLoS One,2015,10(6):e0130894.
[16] DEACON CF.Circulation and degradation of GIP and GLP-1[J].Horm Metab Res,2004,36(11-12):761-765.
[17] BAN K,NOYAN-ASHRAF MH,HOEFER J,et al.Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagonlike peptide 1 receptor-dependent and-independent pathways[J].Circulation,2008,117(18):2340-2350.
[18] WANG Q,BRUBAKER PL.Glucagon-like peptide-1treatment delays the onset of diabetes in8 week-old db/db mice[J].Diabetologia,2002,45(9):1263-1273.
[19] WANG Q,LI L,XU E,et al.Glucagon-like peptide-1regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells[J].Diabetologia,2004,47(3):478-487.
[20] NOYAN-ASHRAF MH,MOMEN MA,BAN K,et al.GLP-1R agonist liraglutide activatescytoprotective pathways and improves outcomes after experimental myocardial infarction in mice[J].Diabetes,2009,58(4):975-983.
[21] DRUCKER DJ.The biology of incretin hormones[J].Cell Metab,2006,3(3):153-165.
[22] CHANG G,ZHANG D,YU H,et al.Cardioprotective effects of exenatide against oxidative stress-induced injury[J].Int J Mol Med,2013,32(5):1011-1020.
[23] BAN K,KIM KH,CHO CK,et al.Glucagon-like peptide(GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39)yet does not require the known GLP-1receptor[J].Endocrinology,2010,151(4):1520-1531.
[24] ERDOGDU O,NATHANSON D,SJOHOLM A,et al.Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-,PKA-and PI3K/Akt-dependent pathways and requires GLP-1 receptor[J].Mol Cell Endocrinol,2010,325(1-2):26-35.
[25] ERDOGDU O,ERIKSSON L,XU H,et al.Exendin-4protects endothelial cells from lipoapoptosis by PKA,PI3K,eNOS,p38 MAPK,and JNK pathways[J].J Mol Endocrinol,2013,50(2):229-241.
[26] HATTORI Y,JOJIMA T,TOMIZAWA A,et al.A glucagon-like peptide-1(GLP-1)analogue,liraglutide,upregulates nitric oxide production and exerts antiinflammatory action in endothelial cells[J].Diabetologia,2010,53(10):2256-2263.
[27] DING L,ZHANG J.Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells[J].Acta Pharmacol Sin,2012,33(1):75-81.
[28] DAI Y,MERCANTI F,DAI D,et al.LOX-1,a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells[J].Biochem Biophys Res Commun,2013,437(1):62-66.
[29] HIRATA Y,KUROBE H,NISHIO C,et al.Exendin-4,a glucagon-like peptide-1 receptor agonist,attenuates neointimal hyperplasia after vascular injury[J].Eur J Pharmacol,2013,699(1-3):106-111.
[30] OESEBURG H,DE BOER RA,BUIKEMA H,et al.Glucagon-like peptide 1 prevents reactive oxygen speciesinduced endothelial cell senescence through the activation of protein kinase A[J].Arterioscler Thromb Vasc Biol,2010,30(7):1407-1414.
[31] SAUVE M,BAN K,MOMEN MA,et al.Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4improves cardiovascularoutcomesaftermyocardial infarction in mice[J].Diabetes,2010,59(4):1063-1073.
[32] BOSE AK,MOCANU MM,CARR RD,et al.Glucagonlike peptide 1 can directly protect the heart against ischemia/reperfusion injury[J].Diabetes,2005,54(1):146-151.
[33] MCCORMICK LM,HOOLE SP,WHITE PA,et al.Pretreatment with glucagon-like peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization[J].JACC Cardiovasc Interv,2015,8(2):292-301.
[34] CERIELLO A,NOVIALS A,ORTEGA E,et al.Glucagon-like peptide 1 reduces endothelial dysfunction,inflammation,and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes[J].Diabetes Care,2013,36(8):2346-2350.
[35] CERIELLO A,NOVIALS A,CANIVELL S,et al.Simultaneous GLP-1 and insulin administration acutely enhancestheirvasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes[J].Diabetes Care,2014,37(7):1938-1943.
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