内皮源性一氧化氮合酶及与糖尿病关系的研究进展
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摘要
糖尿病大血管并发症的主要病变是动脉粥样硬化(AS);APN在AS过程中具有保护作用。内皮源性一氧化氮合酶(eNOS)是APN信号传导通路中的关键分子一氧化氮(NO)的重要合成酶。血管内皮细胞合成的NO除作用于血管平滑肌细胞扩张血管外,还可通过抑制血小板黏附、白细胞趋化及低密度脂蛋白的氧化过程,在糖尿病大血管病变中起保护作用。本文对eNOS及与糖尿病关系的研究进展进行综述。
Atherosclerosis is the main comorbidity in macrovascular complications of diabetes. Adiponectin has a protection effect in the pathogenesis of atherosclerosis. Endothelial nitric oxide synthase(eNOS)is a key molecule in the adiponectin signal transduction pathway and nitric oxide(NO)production.NO,which is produced by vascular endothelial cells,could dilate vessels and exert a protection function in macrovascular complications of diabetes via inhibiting platelet adherence,leukocyte chemotaxis and low-density lipoprotein oxidation. This article briefly reviewed the recent researches of eNOS and its relation with diabetes comorbidities.
Atherosclerosis is the main comorbidity in macrovascular complications of diabetes. Adiponectin has a protection effect in the pathogenesis of atherosclerosis. Endothelial nitric oxide synthase(eNOS)is a key molecule in the adiponectin signal transduction pathway and nitric oxide(NO)production.NO,which is produced by vascular endothelial cells,could dilate vessels and exert a protection function in macrovascular complications of diabetes via inhibiting platelet adherence,leukocyte chemotaxis and low-density lipoprotein oxidation. This article briefly reviewed the recent researches of eNOS and its relation with diabetes comorbidities.
引文
[1]Yang WS,Jeng CY,Wu TJ,et al.Synthetic peroxisome proliferator-activated receptor-gamma agonist,rosiglitazone,increases plasma levels of adiponectin in type 2 diabetic patients.Diabetes Care,2002,25:376-380.
[2]Cama SF,Sekurib C,Tengizc I,et al.The G894T polymorphism on endothelial nitric oxide synthase gene is associated with premature coronary artery disease in a Turkish population.Thrombosis Research,2005,116:287-292.
[3]Ignarro LJ,Harbison RG,Wood KS,et al.Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein:stimulation by acetylcho-line,bradykinin and arachidonic acid.J Pharmacol Exp Ther,1986,237:893-900.
[4]Fleming I,Fisslthaler B,Dimmeler S,et al.Phosphorylation of Thr495 regulates Ca~(2+)/calmodulin-dependent endothelial nitric oxide synthase activity.Circ Res,2001,88:e68-e75.
[5]Fleming I.Molecular mechanisms underlying the activation of eNOS.Pflugers Arch,2010,459:793-806.
[6]Dudzinski DM,Igarashi J,Greif D,et al.The regulation and pharmacology of endothelial nitric oxide synthase.Annu Rev Pharmacol Toxicol,2006,46:235-276.
[7]Kim F,Gallis B,Corson MA.TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells.Am J Physiol Cell Physiol,2001,280:C1057-C1065.
[8]Shen YH,Zhang L,Gan Y,et al.Up-regulation of PTEN(phosphatase and tensin homolog deleted on chromosome ten)mediates p38 MAPK stress signal-induced inhibition of insulin sig-naling.A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells.J Biol Chem,2006,281:7727-7736.
[9]Fisslthaler B,Fleming I.Activation and signaling by the AMP-activated protein kinase in endothelial cells.Circ Res,2009,105:114-127.
[10]Schulz E,Anter E,Zou MH,et al.Estradiolmediated endothelial nitric oxide synthase association with heat shock protein 90 re-quires adenosine monophosphate-dependent protein kinase.Circu-lation,2005,111:3473-3480.
[11]Dimmeler S,Fleming I,Fisslthaler B,et al.Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphoryla-tion.Nature,1999,399:601-605.
[12]Fulton D,Gratton JP,Mccabe TJ,et al.Regulation of endothe-lium-derived nitric oxide production by the protein kinase Akt.Nature,1999,399:597-601.
[13]Fleming I,Fisslthaler B,Dimmeler S,et al.Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity.Circ Res,2001,88:e68-e75.
[14]Wagner L,Laczy B,TamaskóM,et al.Cigarette smoke-induced alterations in endothelial nitric oxide synthase phosphorylation:role of protein kinase C.J Endo Cell Res,2007,14:245-255.
[15]Moncada S,Higgs A.The L-arginine-nitric oxide pathway.New Engl J Med,1993,329:2002-2012.
[16]Atochin DN,Demchenko IT,Astern J,et al.Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia.J Cereb Blood Flow Metab,2003,23:1219-1226.
[17]Matsuda T,Bates JN,Lewis SJ,et al.Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine.Circ Res,1995,76:426-433.
[18]Duplain H,Burcelin R,Sartori C,et al.Insulin resistance,hyperlipidemia,and hypertension in mice lacking endothelial nitric oxide synthase.Circulation,2001,104:342-345.
[19]Radomski MW,Palmer RM,Moncada S.Modulation of platelet aggregation by an L-arginine-nitric oxide pathway.Trends Phar-macol Sci,1991,12:87-88.
[20]Kariya K,Kawahara Y,Araki S,et al.Antiproliferative action of cyclic GMP-elevating vasodilators in cultured rabbit aortic smooth muscle cells.Atherosclerosis,1989,80:143-147.
[21]Moroi M,Zhang L,Yasuda T,et al.Interaction of genetic deficien-cy of endothelial nitric oxide,gender,and pregnancy in vascular re-sponse to injury in mice.J Clin Invest,1998,101:1225-1232.
[22]De Caterina R,Libby P,Peng HB,et al.Nitric oxide decreases cytokine-induced endothelial activation.Nitric oxide selectively reduces endothelial expression of adhesion molecules and proin-flammatory cytokines.J Clin Invest,1995,96:60-68.
[23]Williams IL,Wheatcroft SB,Shah AM,et al.Obesity,athero-sclerosis and the vascular endothelium:mechanisms of reduced nitric oxide bioavailability in obese humans.Int J Obes Relat Metab Disord,2002,26:754-764.
[24]Adela R,Nethi SK,Bagul PK,et al.Hyperglycaemia enhances nitric oxide production in diabetes:a study from South Indian pa-tients.PLoS One,2015,10:e0125270.
[25]De Vriese AS,Verbeuren TJ,Van de Voorde J,et al.Endothelial dysfunction in diabetes.Br J Pharmacol,2000,130:963-974.
[26]Scherrer U,Randin D,Vollenweider P,et al.Nitric oxide release accounts for insulin's vascular effects in humans.J Clin In-vest,1994,94:2511-2515.
[27]Lafuente N,Matesanz N,Azcutia V,et al.The deleterious effect of high concentrations of D-glucose requires pro-inflammato-ry preconditioning.J Hypertens,2008,26:478-485.
[28]Straub SV,Girouard H,Doetsch PE,et al.Regulation of intracerebral arteriolar tone by K(v)channels:effects of glucose and PKC.Am J Physiol Cell Physiol,2009,297:C788-C796.
[29]Ding Y,Vaziri ND,Coulson R,et al.Effects of simulated hyperglycemia,insulin,and glucagon on endothelial nitric oxide synthase expression.Am J Physiol Endocrinol Metab,2000,279:E11-E17.
[30]Okon EB,Chung AW,Rauniyar P,et al.Compromised arterial function in human type 2 diabetic patients.Diabetes,2005,54:2415-2423.
[31]Aljofan M,Triggle CR,Ding H.Oxidative stress and increased eNOS and NADPH oxidase expression in mouse microvessel en-dothelial cells.J Cell Physiol,2007,212:682-689.
[32]Aljofan M,Ding H.High glucose increases expression of cyclo-oxygenase-2,increases oxidative stress and decreases the genera-tion of nitric oxide in mouse microvessel endothelial cells.J Cell Physiol,2010,222:669-675.
[33]Kuboki K,Jiang ZY,Takahara N,et al.Regulation of endothelial constitutive nitric oxide synthase gene expression in endotheli-al cells and in vivo:a specific vascular action of insulin.Circula-tion,2000,101:676-681.
[34]Forstermann U,Sessa WC.Nitric oxide synthases:regulation and function.Eur Heart J.2012,33:829-837,837a.
[35]Dimmeler S,Zeiher AM.Nitric oxide-an endothelial cell survival factor.Cell Death Differ,1999,6:964-968.
[36]Li H,Forstermann U.Prevention of atherosclerosis by interference with the vascular nitric oxide system.Curr Pharm Des,2009,15:3133-3145.
[37]Abudukadier A,Fujita Y,Obara A,et al.Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogen-esis in an endothelial nitric oxide synthase-dependent manner in diabetic mice.Diabetes,2013,62:3033-3043.
[38]Adel H,Taye A,Hkalifa MM.Spironolactone improves endo-thelial dysfunction in streptozotocin-induced diabetic rats.Naunyn Schmiedebergs Arch Pharmacol,2014,387:1187-1197.
[39]白莲,李春君,邢云芝,等.利拉鲁肽激活糖尿病大鼠肾脏内皮源性一氧化氮合酶活性降低尿白蛋白排泄的研究.中国糖尿病杂志,2014,22:846-849.
[40]Liu B,Kuang L,Liu J.Bariatric surgery relieves type 2 diabetes and modulates inflammatory factors and coronary endothelium eNOS/iNOS expression in db/db mice.Can J Physiol Pharma-col,2014,92:70-77.
[41]Li JY,Tao F,Wu XX,et al.Polymorphic variations in manganese superoxide dismutase(MnSOD)and endothelial nitric oxide synthase(eNOS)genes contribute to the development of type 2diabetes mellitus in the Chinese Han population.Genet Mol Res,2015,14:12993-13002.
[42]Qian-Qian Y,Yong Y,Jing Z,et al.Association between a 27-bp variable number of tandem repeat polymorphism in intron 4 of the eNOS gene and risk of diabetic retinopathy type 2 diabetes mellitus:a meta-analysis.Curr Eye Res,2014:39:1052-1058.
[43]Rahimi Z,Rahimi Z,Shahvaisi-Zadeh F,et al.eNOS 4a/b polymorphism and its interaction with eNOS G894T variants in type 2 diabetes mellitus:modifying the risk of diabetic nephropa-thy.Dis Markers,2013,34:437-443.
[44]Ma X,Bai G,Lu D,et al.Association between STK11 gene polymorphisms and coronary artery disease in type 2 diabetes in Han population in China.J Diabetes Res,2017,6297087.
[2]Cama SF,Sekurib C,Tengizc I,et al.The G894T polymorphism on endothelial nitric oxide synthase gene is associated with premature coronary artery disease in a Turkish population.Thrombosis Research,2005,116:287-292.
[3]Ignarro LJ,Harbison RG,Wood KS,et al.Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein:stimulation by acetylcho-line,bradykinin and arachidonic acid.J Pharmacol Exp Ther,1986,237:893-900.
[4]Fleming I,Fisslthaler B,Dimmeler S,et al.Phosphorylation of Thr495 regulates Ca~(2+)/calmodulin-dependent endothelial nitric oxide synthase activity.Circ Res,2001,88:e68-e75.
[5]Fleming I.Molecular mechanisms underlying the activation of eNOS.Pflugers Arch,2010,459:793-806.
[6]Dudzinski DM,Igarashi J,Greif D,et al.The regulation and pharmacology of endothelial nitric oxide synthase.Annu Rev Pharmacol Toxicol,2006,46:235-276.
[7]Kim F,Gallis B,Corson MA.TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells.Am J Physiol Cell Physiol,2001,280:C1057-C1065.
[8]Shen YH,Zhang L,Gan Y,et al.Up-regulation of PTEN(phosphatase and tensin homolog deleted on chromosome ten)mediates p38 MAPK stress signal-induced inhibition of insulin sig-naling.A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells.J Biol Chem,2006,281:7727-7736.
[9]Fisslthaler B,Fleming I.Activation and signaling by the AMP-activated protein kinase in endothelial cells.Circ Res,2009,105:114-127.
[10]Schulz E,Anter E,Zou MH,et al.Estradiolmediated endothelial nitric oxide synthase association with heat shock protein 90 re-quires adenosine monophosphate-dependent protein kinase.Circu-lation,2005,111:3473-3480.
[11]Dimmeler S,Fleming I,Fisslthaler B,et al.Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphoryla-tion.Nature,1999,399:601-605.
[12]Fulton D,Gratton JP,Mccabe TJ,et al.Regulation of endothe-lium-derived nitric oxide production by the protein kinase Akt.Nature,1999,399:597-601.
[13]Fleming I,Fisslthaler B,Dimmeler S,et al.Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity.Circ Res,2001,88:e68-e75.
[14]Wagner L,Laczy B,TamaskóM,et al.Cigarette smoke-induced alterations in endothelial nitric oxide synthase phosphorylation:role of protein kinase C.J Endo Cell Res,2007,14:245-255.
[15]Moncada S,Higgs A.The L-arginine-nitric oxide pathway.New Engl J Med,1993,329:2002-2012.
[16]Atochin DN,Demchenko IT,Astern J,et al.Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia.J Cereb Blood Flow Metab,2003,23:1219-1226.
[17]Matsuda T,Bates JN,Lewis SJ,et al.Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine.Circ Res,1995,76:426-433.
[18]Duplain H,Burcelin R,Sartori C,et al.Insulin resistance,hyperlipidemia,and hypertension in mice lacking endothelial nitric oxide synthase.Circulation,2001,104:342-345.
[19]Radomski MW,Palmer RM,Moncada S.Modulation of platelet aggregation by an L-arginine-nitric oxide pathway.Trends Phar-macol Sci,1991,12:87-88.
[20]Kariya K,Kawahara Y,Araki S,et al.Antiproliferative action of cyclic GMP-elevating vasodilators in cultured rabbit aortic smooth muscle cells.Atherosclerosis,1989,80:143-147.
[21]Moroi M,Zhang L,Yasuda T,et al.Interaction of genetic deficien-cy of endothelial nitric oxide,gender,and pregnancy in vascular re-sponse to injury in mice.J Clin Invest,1998,101:1225-1232.
[22]De Caterina R,Libby P,Peng HB,et al.Nitric oxide decreases cytokine-induced endothelial activation.Nitric oxide selectively reduces endothelial expression of adhesion molecules and proin-flammatory cytokines.J Clin Invest,1995,96:60-68.
[23]Williams IL,Wheatcroft SB,Shah AM,et al.Obesity,athero-sclerosis and the vascular endothelium:mechanisms of reduced nitric oxide bioavailability in obese humans.Int J Obes Relat Metab Disord,2002,26:754-764.
[24]Adela R,Nethi SK,Bagul PK,et al.Hyperglycaemia enhances nitric oxide production in diabetes:a study from South Indian pa-tients.PLoS One,2015,10:e0125270.
[25]De Vriese AS,Verbeuren TJ,Van de Voorde J,et al.Endothelial dysfunction in diabetes.Br J Pharmacol,2000,130:963-974.
[26]Scherrer U,Randin D,Vollenweider P,et al.Nitric oxide release accounts for insulin's vascular effects in humans.J Clin In-vest,1994,94:2511-2515.
[27]Lafuente N,Matesanz N,Azcutia V,et al.The deleterious effect of high concentrations of D-glucose requires pro-inflammato-ry preconditioning.J Hypertens,2008,26:478-485.
[28]Straub SV,Girouard H,Doetsch PE,et al.Regulation of intracerebral arteriolar tone by K(v)channels:effects of glucose and PKC.Am J Physiol Cell Physiol,2009,297:C788-C796.
[29]Ding Y,Vaziri ND,Coulson R,et al.Effects of simulated hyperglycemia,insulin,and glucagon on endothelial nitric oxide synthase expression.Am J Physiol Endocrinol Metab,2000,279:E11-E17.
[30]Okon EB,Chung AW,Rauniyar P,et al.Compromised arterial function in human type 2 diabetic patients.Diabetes,2005,54:2415-2423.
[31]Aljofan M,Triggle CR,Ding H.Oxidative stress and increased eNOS and NADPH oxidase expression in mouse microvessel en-dothelial cells.J Cell Physiol,2007,212:682-689.
[32]Aljofan M,Ding H.High glucose increases expression of cyclo-oxygenase-2,increases oxidative stress and decreases the genera-tion of nitric oxide in mouse microvessel endothelial cells.J Cell Physiol,2010,222:669-675.
[33]Kuboki K,Jiang ZY,Takahara N,et al.Regulation of endothelial constitutive nitric oxide synthase gene expression in endotheli-al cells and in vivo:a specific vascular action of insulin.Circula-tion,2000,101:676-681.
[34]Forstermann U,Sessa WC.Nitric oxide synthases:regulation and function.Eur Heart J.2012,33:829-837,837a.
[35]Dimmeler S,Zeiher AM.Nitric oxide-an endothelial cell survival factor.Cell Death Differ,1999,6:964-968.
[36]Li H,Forstermann U.Prevention of atherosclerosis by interference with the vascular nitric oxide system.Curr Pharm Des,2009,15:3133-3145.
[37]Abudukadier A,Fujita Y,Obara A,et al.Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogen-esis in an endothelial nitric oxide synthase-dependent manner in diabetic mice.Diabetes,2013,62:3033-3043.
[38]Adel H,Taye A,Hkalifa MM.Spironolactone improves endo-thelial dysfunction in streptozotocin-induced diabetic rats.Naunyn Schmiedebergs Arch Pharmacol,2014,387:1187-1197.
[39]白莲,李春君,邢云芝,等.利拉鲁肽激活糖尿病大鼠肾脏内皮源性一氧化氮合酶活性降低尿白蛋白排泄的研究.中国糖尿病杂志,2014,22:846-849.
[40]Liu B,Kuang L,Liu J.Bariatric surgery relieves type 2 diabetes and modulates inflammatory factors and coronary endothelium eNOS/iNOS expression in db/db mice.Can J Physiol Pharma-col,2014,92:70-77.
[41]Li JY,Tao F,Wu XX,et al.Polymorphic variations in manganese superoxide dismutase(MnSOD)and endothelial nitric oxide synthase(eNOS)genes contribute to the development of type 2diabetes mellitus in the Chinese Han population.Genet Mol Res,2015,14:12993-13002.
[42]Qian-Qian Y,Yong Y,Jing Z,et al.Association between a 27-bp variable number of tandem repeat polymorphism in intron 4 of the eNOS gene and risk of diabetic retinopathy type 2 diabetes mellitus:a meta-analysis.Curr Eye Res,2014:39:1052-1058.
[43]Rahimi Z,Rahimi Z,Shahvaisi-Zadeh F,et al.eNOS 4a/b polymorphism and its interaction with eNOS G894T variants in type 2 diabetes mellitus:modifying the risk of diabetic nephropa-thy.Dis Markers,2013,34:437-443.
[44]Ma X,Bai G,Lu D,et al.Association between STK11 gene polymorphisms and coronary artery disease in type 2 diabetes in Han population in China.J Diabetes Res,2017,6297087.