脂联素在肺动脉高压发病中的作用机制研究进展
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摘要
人脂联素(APN)是一种含有244个氨基酸的糖蛋白,主要由脂肪细胞分泌。现已发现APN至少有4种受体:脂联素受体1、脂联素受体2、T-钙黏蛋白和钙网蛋白/CD91共受体。APN与受体结合可发挥多种生理功能,影响糖类和脂肪代谢,具有抗炎和抗平滑肌增殖等作用。肺动脉高压(PAH)是一种慢性进行性心血管疾病,以大量的肺组织中小动脉压力增高为特征,发病率和死亡率均较高。炎症在PAH病程中发挥着重要的作用,可能参与疾病的病理损伤。近年来的研究发现,APN和PAH的发病关系密切,APN可能通过多方面机制减缓PAH的病程进展。本文重点围绕APN通过抗炎和抗血管平滑肌增殖的作用来减缓PAH发展的机制新进展做一综述。
Adiponectin( APN) is a glycoprotein containing 244 amino acids,which is mainly secreted by adipocytes. There are at least four kinds of APN receptors: adiponectin receptor 1,adiponectin receptor 2,T-cadherin and calreticulin/CD91. APN could play multifunctional roles in the process of physiology via binding to its receptors,including the relugulation of carbohydrates and fats metabolism,the control of inflammation and the inhibition of smooth muscle proliferation. Pulmonary artery hypertension( PAH) is a chronic and progressive cardiopulmonary disease with high morbidity and mortality,which is characterised by the increasing of pressure in the extensive small to mid-sized pulmonary arterioles. Inflammation may contribute to the pathological injury of PAH. Recent study results showed that APN was closely related to the pathogenesis of PAH and may slow disease progression by its multifunctional effects. This paper mainly focuses on the advance that APN suppress the PAH progression through the control of inflammation and the inhibition of smooth muscle proliferation.
Adiponectin( APN) is a glycoprotein containing 244 amino acids,which is mainly secreted by adipocytes. There are at least four kinds of APN receptors: adiponectin receptor 1,adiponectin receptor 2,T-cadherin and calreticulin/CD91. APN could play multifunctional roles in the process of physiology via binding to its receptors,including the relugulation of carbohydrates and fats metabolism,the control of inflammation and the inhibition of smooth muscle proliferation. Pulmonary artery hypertension( PAH) is a chronic and progressive cardiopulmonary disease with high morbidity and mortality,which is characterised by the increasing of pressure in the extensive small to mid-sized pulmonary arterioles. Inflammation may contribute to the pathological injury of PAH. Recent study results showed that APN was closely related to the pathogenesis of PAH and may slow disease progression by its multifunctional effects. This paper mainly focuses on the advance that APN suppress the PAH progression through the control of inflammation and the inhibition of smooth muscle proliferation.
引文
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[15] Lyle MA,Davis JP,Brozovich FV. Regulation of pulmonary vascular smooth muscle contractility in pulmonary arterial hypertension:implications for therapy[J]. Front Physiol,2017,8:614.
[16] Jafri S, Ormiston ML. Immune regulation of systemic hypertension,pulmonary arterial hypertension,and preeclampsia:shared disease mechanisms and translational opportunities[J].Am J Physiol Regul Integr Comp Physiol,2017,313(6):R693-R705.
[17] Biernacka A,Frangogiannis NG. Aging and cardiac fibrosis[J].Aging Dis,2011,2(2):158-173.
[18] Pezzuto B,Badagliacca R,Poscia R,et al. Circulating biomarkers in pulmonary arterial hypertension:update and future direction[J]. J Heart Lung Transplant,2015,34(3):282-305.
[19]郑亚国,何建国,熊长明.肺动脉高压免疫炎症机制研究进展[J].中国循环杂志,2013,28(6):469-471.Zheng YG,He JG,Xiong CM. Research progress of pulmonary arterial hypertension immune inflammatory mechanism[J]. Chin Circul J,2013,28(6):469-471.
[20] Murtha LA,Schuliga MJ,Mabotuwana NS,et al. The processes and mechanisms of cardiac and pulmonary fibrosis[J]. Front Physiol,2017,8:777.
[21] Frangogiannis NG. The inflammatory response in myocardial injury,repair,and remodelling[J]. Nat Rev Cardiol,2014,11(5):255-265.
[22] Summer R,Fiack CA,Ikeda Y,et al. Adiponectin deficiency:a model of pulmonary hypertension associated with pulmonary vascular disease[J]. Am J Physiol Lung Cell Mol Physiol,2009,297(3):L432-L438.
[23] Mori T,Koyama Y,Maeda N,et al. Ultrastructural localization of adiponectin protein in vasculature of normal and atherosclerotic mice[J]. Scientific reports,2014,4:4895.
[24] Weng M,Raher MJ,Leyton P,et al. Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension[J]. Am J Respiratory Cell Mole Biol,2011,45(2):340-347.
[25] Aldhahi W, Hamdy O. Adipokines, inflammation, and the endothelium in diabetes[J]. Current Diabetes Reports,2003,3(4):293-298.
[26] Luo Y,Liu M. Adiponectin:a versatile player of innate immunity[J]. Journal of molecular cell biology,2016,8(2):120-128.
[27] Du Y,Li R,Lau WB,et al. Adiponectin at physiologically relevant concentrations enhances the vasorelaxative effect of acetylcholine via Cav-1/AdipoR-1 signaling[J]. PLo S One,2016,11(3):e0152247.
[28] Konter JM,Parker JL,Baez E,et al. Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation[J]. J Immunol,2012,188(2):854-863.
[29] Ouchi N,Kihara S,Arita Y,et al. Adiponectin,an adipocytederived plasma protein,inhibits endothelial NF-kappaB signaling through a c AMP-dependent pathway[J]. Circulation,2000,102(11):1296-1301.
[30] Takemura Y,Ouchi N,Shibata R,et al. Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies[J]. J Clin Invest,2007,117(2):375-386.
[31] Ouchi N,Parker JL,Lugus JJ,et al. Adipokines in inflammation and metabolic disease[J]. Nat Rev Immunol,2011,11(2):85-97.
[32] Woodward L,Akoumianakis I,Antoniades C. Unravelling the adiponectin paradox:novel roles of adiponectin in the regulation of cardiovascular disease[J]. Br J Pharmacol,2017,174(22):4007-20.
[33] Fruhbeck G,Catalan V,Rodriguez A,et al. Involvement of the leptin-adiponectin axis in inflammation and oxidative stress in the metabolic syndrome[J]. Scientific Rep,2017,7(1):6619.
[34] Robinson K,Prins J,Venkatesh B. Clinical review:adiponectin biology and its role in inflammation and critical illness[J].Critical Care,2011,15(2):221.
[35]葛倩,邓华聪,刘金波.脂联素对血管内皮功能的影响[J].中华内分泌代谢杂志,2006,22(1):15-18.Ge Q,Deng HC,Liu JB. Effect of adiponectin on endothelial function[J]. Chin J Endocrinol Metab,2006,22(1):15-18.
[36] Wang X,Chen Q,Pu H,et al. Adiponectin improves NF-kappaBmediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice[J]. Lipids Health Dise,2016,15:33.
[37] Song J,Choi SM,Kim BC. Adiponectin Regulates the Polarization and Function of Microglia via PPAR-gamma Signaling Under Amyloid beta Toxicity[J]. Front Cell Neuroscience,2017,11:64.
[38]刘利梅,赵亚莉,李丽.脂联素的信号转导通路[J].生理科学进展,2005,36(2):130-132.Liu LM,Zhao LY,Li L. The signal transduction pathway of Adiponectin[J]. J Physiol Sci,2005,36(2):130-132.
[39] Hansmann G,Wagner RA,Schellong S,et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation[J].Circulation,2007,115(10):1275-1284.
[40] Lee FP,Jen CY,Chang CC,et al. Mechanisms of adiponectinmediated COX-2 induction and protection against iron injury in mouse hepatocytes[J]. J Cell Physiol,2010,224(3):837-847.
[41] Planavila A,Alegret M,Sanchez RM,et al. Increased Akt protein expression is associated with decreased ceramide content in skeletal muscle of troglitazone-treated mice[J]. Biochem Pharmacol,2005,69(8):1195-1204.
[42]吴新丹,刘斌.肺血管平滑肌增殖的研究进展[J].西南军医,2013,4:399-402.Wu XD,Liu B. Progress in the proliferation of pulmonary vascular smooth muscle[J]. J Military Surg Southwest China,2013,4:399-402.
[43]胡耀东,王治平,李启富.脂联素对血管紧张素Ⅱ诱导血管平滑肌细胞分化和增殖的影响[J].长治医学院学报,2016,30(3):179-182.Hu YD,Wang ZP,Li QF. The effection of adiponectin to angiotensinⅡinduced vascular smooth muscle cell differentiation and proliferation[J]. J Changzhi Med College,2016,30(3):179-182.
[44] Arita Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell[J]. Circulation,2002,105(24):2893-2898.
[45] Kubota N,Terauchi Y,Yamauchi T,et al. Disruption of adiponectin causes insulin resistance and neointimal formation[J]. J Biol Chem,2002,277(29):25863-6.
[46] Qi GM,Jia LX,Li YL,et al. Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy[J]. Endocrinology,2014,155(6):2254-65.
[47] Luke T,Maylor J,Undem C,et al. Kinase-dependent activation of voltage-gated Ca2+channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia[J]. Am J Physiol Lung Cell Mole Physiol,2012,302(10):L1128-39.
[48] Rzucidlo EM,Martin KA,Powell RJ. Regulation of vascular smooth muscle cell differentiation[J]. J Vascular Surg,2007,45(Suppl A):A25-A32.
[49] Ding M,Xie Y,Wagner RJ,et al. Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and Fox O4[J]. Arterioscler Thrombo Vasc Biol,2011,31(6):1403-1410.
[50] Mathew R. Cell-specific dual role of caveolin-1 in pulmonary hypertension[J]. Pulmonary Med,2011,2011:573432.
[51] Nakagawa Y,Kishida K,Kihara S,et al. Adiponectin ameliorates hypoxia-induced pulmonary arterial remodeling[J]. Biochem Biophy Res Commun,2009,382(1):183-188.
[52] Toussirot E,Binda D,Gueugnon C,et al. Adiponectin in autoimmune diseases[J]. Current Med Chem,2012,19(32):5474-5480.
[53] Kochetkova EA,Nevsorova VA,Ugay LG,et al. Issues of adipokine regulation in idiopathic pulmonary arterial hypertension and systemic osteopenia[J]. Kardiologiia,2018,2:17-23.
[54] Kochetkova EA,Ugai LG,Maistrovskaia YV,et al. Adipokines:a possible contribution to vascular and bone remodeling in idiopathic pulmonary arterial hypertension[J]. Calcified Tissue Internat,2017,100(4):325-331.
[2] Santos M,Reis A,Goncalves F,et al. Adiponectin levels are elevated in patients with pulmonary arterial hypertension[J].Clinical Cardiol,2014,37(1):21-25.
[3] Kharroubi I,Rasschaert J,Eizirik DL,et al. Expression of adiponectin receptors in pancreatic beta cells[J]. Biochem Biophy Res Commun,2003,312(4):1118-1122.
[4] Nakatsuji H,Kobayashi H,Kishida K,et al. Binding of adiponectin and C1q in human serum,and clinical significance of the measurement of C1q-adiponectin/total adiponectin ratio[J]. Metabolism,2013,62(1):109-120.
[5] Tang K,Zhang C. Sustained high levels of both total and high molecular weight adiponectin in plasma during the convalescent phase of haemorrhagic fever with renal syndrome are associated with disease severity[J]. J Immunol Res,2017,2017:6468097.
[6] Freitas Lima LC,Braga VA,do Socorro de Franca Silva M,et al.Adipokines, diabetes and atherosclerosis:an inflammatory association[J]. Front Physiol,2015,6:304.
[7] Alzahrani B,Iseli T,Ramezani-Moghadam M,et al. The role of AdipoR1 and AdipoR2 in liver fibrosis[J]. Biochimica Biophysica Acta Mol Basis Dis,2018,1864(3):700-708.
[8] Debard C,Laville M,Berbe V,et al. Expression of key genes of fatty acid oxidation,including adiponectin receptors,in skeletal muscle of Type 2 diabetic patients[J]. Diabetologia,2004,47(5):917-925.
[9] Wang L,Xue K,Wang Y,et al. Molecular and functional characterization of the adiponectin(AdipoQ)gene in goat skeletal muscle satellite cells[J]. Asian-Australas J Animal Sciences,2018,PMID:29381891.
[10] Chinetti G,Zawadski C,Fruchart JC,et al. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha,PPARgamma,and LXR[J]. Bioche Biophy Res Commun,2004,314(1):151-158.
[11] Ding ST,Liu BH,Ko YH. Cloning and expression of porcine adiponectin and adiponectin receptor 1 and 2 genes in pigs[J]. J Animal Sci,2004,82(11):3162-3174.
[12] Berner HS,Lyngstadaas SP,Spahr A,et al. Adiponectin and its receptors are expressed in bone-forming cells[J]. Bone,2004,35(4):842-849.
[13] Wang ZV,Scherer PE. Adiponectin,the past two decades[J]. J Mol Cell Biol,2016,8(2):93-100.
[14] Denzel MS,Scimia MC,Zumstein PM,et al. T-cadherin is critical for adiponectin-mediated cardioprotection in mice[J]. J Clin Invest,2010,120(12):4342-52.
[15] Lyle MA,Davis JP,Brozovich FV. Regulation of pulmonary vascular smooth muscle contractility in pulmonary arterial hypertension:implications for therapy[J]. Front Physiol,2017,8:614.
[16] Jafri S, Ormiston ML. Immune regulation of systemic hypertension,pulmonary arterial hypertension,and preeclampsia:shared disease mechanisms and translational opportunities[J].Am J Physiol Regul Integr Comp Physiol,2017,313(6):R693-R705.
[17] Biernacka A,Frangogiannis NG. Aging and cardiac fibrosis[J].Aging Dis,2011,2(2):158-173.
[18] Pezzuto B,Badagliacca R,Poscia R,et al. Circulating biomarkers in pulmonary arterial hypertension:update and future direction[J]. J Heart Lung Transplant,2015,34(3):282-305.
[19]郑亚国,何建国,熊长明.肺动脉高压免疫炎症机制研究进展[J].中国循环杂志,2013,28(6):469-471.Zheng YG,He JG,Xiong CM. Research progress of pulmonary arterial hypertension immune inflammatory mechanism[J]. Chin Circul J,2013,28(6):469-471.
[20] Murtha LA,Schuliga MJ,Mabotuwana NS,et al. The processes and mechanisms of cardiac and pulmonary fibrosis[J]. Front Physiol,2017,8:777.
[21] Frangogiannis NG. The inflammatory response in myocardial injury,repair,and remodelling[J]. Nat Rev Cardiol,2014,11(5):255-265.
[22] Summer R,Fiack CA,Ikeda Y,et al. Adiponectin deficiency:a model of pulmonary hypertension associated with pulmonary vascular disease[J]. Am J Physiol Lung Cell Mol Physiol,2009,297(3):L432-L438.
[23] Mori T,Koyama Y,Maeda N,et al. Ultrastructural localization of adiponectin protein in vasculature of normal and atherosclerotic mice[J]. Scientific reports,2014,4:4895.
[24] Weng M,Raher MJ,Leyton P,et al. Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension[J]. Am J Respiratory Cell Mole Biol,2011,45(2):340-347.
[25] Aldhahi W, Hamdy O. Adipokines, inflammation, and the endothelium in diabetes[J]. Current Diabetes Reports,2003,3(4):293-298.
[26] Luo Y,Liu M. Adiponectin:a versatile player of innate immunity[J]. Journal of molecular cell biology,2016,8(2):120-128.
[27] Du Y,Li R,Lau WB,et al. Adiponectin at physiologically relevant concentrations enhances the vasorelaxative effect of acetylcholine via Cav-1/AdipoR-1 signaling[J]. PLo S One,2016,11(3):e0152247.
[28] Konter JM,Parker JL,Baez E,et al. Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation[J]. J Immunol,2012,188(2):854-863.
[29] Ouchi N,Kihara S,Arita Y,et al. Adiponectin,an adipocytederived plasma protein,inhibits endothelial NF-kappaB signaling through a c AMP-dependent pathway[J]. Circulation,2000,102(11):1296-1301.
[30] Takemura Y,Ouchi N,Shibata R,et al. Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies[J]. J Clin Invest,2007,117(2):375-386.
[31] Ouchi N,Parker JL,Lugus JJ,et al. Adipokines in inflammation and metabolic disease[J]. Nat Rev Immunol,2011,11(2):85-97.
[32] Woodward L,Akoumianakis I,Antoniades C. Unravelling the adiponectin paradox:novel roles of adiponectin in the regulation of cardiovascular disease[J]. Br J Pharmacol,2017,174(22):4007-20.
[33] Fruhbeck G,Catalan V,Rodriguez A,et al. Involvement of the leptin-adiponectin axis in inflammation and oxidative stress in the metabolic syndrome[J]. Scientific Rep,2017,7(1):6619.
[34] Robinson K,Prins J,Venkatesh B. Clinical review:adiponectin biology and its role in inflammation and critical illness[J].Critical Care,2011,15(2):221.
[35]葛倩,邓华聪,刘金波.脂联素对血管内皮功能的影响[J].中华内分泌代谢杂志,2006,22(1):15-18.Ge Q,Deng HC,Liu JB. Effect of adiponectin on endothelial function[J]. Chin J Endocrinol Metab,2006,22(1):15-18.
[36] Wang X,Chen Q,Pu H,et al. Adiponectin improves NF-kappaBmediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice[J]. Lipids Health Dise,2016,15:33.
[37] Song J,Choi SM,Kim BC. Adiponectin Regulates the Polarization and Function of Microglia via PPAR-gamma Signaling Under Amyloid beta Toxicity[J]. Front Cell Neuroscience,2017,11:64.
[38]刘利梅,赵亚莉,李丽.脂联素的信号转导通路[J].生理科学进展,2005,36(2):130-132.Liu LM,Zhao LY,Li L. The signal transduction pathway of Adiponectin[J]. J Physiol Sci,2005,36(2):130-132.
[39] Hansmann G,Wagner RA,Schellong S,et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation[J].Circulation,2007,115(10):1275-1284.
[40] Lee FP,Jen CY,Chang CC,et al. Mechanisms of adiponectinmediated COX-2 induction and protection against iron injury in mouse hepatocytes[J]. J Cell Physiol,2010,224(3):837-847.
[41] Planavila A,Alegret M,Sanchez RM,et al. Increased Akt protein expression is associated with decreased ceramide content in skeletal muscle of troglitazone-treated mice[J]. Biochem Pharmacol,2005,69(8):1195-1204.
[42]吴新丹,刘斌.肺血管平滑肌增殖的研究进展[J].西南军医,2013,4:399-402.Wu XD,Liu B. Progress in the proliferation of pulmonary vascular smooth muscle[J]. J Military Surg Southwest China,2013,4:399-402.
[43]胡耀东,王治平,李启富.脂联素对血管紧张素Ⅱ诱导血管平滑肌细胞分化和增殖的影响[J].长治医学院学报,2016,30(3):179-182.Hu YD,Wang ZP,Li QF. The effection of adiponectin to angiotensinⅡinduced vascular smooth muscle cell differentiation and proliferation[J]. J Changzhi Med College,2016,30(3):179-182.
[44] Arita Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell[J]. Circulation,2002,105(24):2893-2898.
[45] Kubota N,Terauchi Y,Yamauchi T,et al. Disruption of adiponectin causes insulin resistance and neointimal formation[J]. J Biol Chem,2002,277(29):25863-6.
[46] Qi GM,Jia LX,Li YL,et al. Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy[J]. Endocrinology,2014,155(6):2254-65.
[47] Luke T,Maylor J,Undem C,et al. Kinase-dependent activation of voltage-gated Ca2+channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia[J]. Am J Physiol Lung Cell Mole Physiol,2012,302(10):L1128-39.
[48] Rzucidlo EM,Martin KA,Powell RJ. Regulation of vascular smooth muscle cell differentiation[J]. J Vascular Surg,2007,45(Suppl A):A25-A32.
[49] Ding M,Xie Y,Wagner RJ,et al. Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and Fox O4[J]. Arterioscler Thrombo Vasc Biol,2011,31(6):1403-1410.
[50] Mathew R. Cell-specific dual role of caveolin-1 in pulmonary hypertension[J]. Pulmonary Med,2011,2011:573432.
[51] Nakagawa Y,Kishida K,Kihara S,et al. Adiponectin ameliorates hypoxia-induced pulmonary arterial remodeling[J]. Biochem Biophy Res Commun,2009,382(1):183-188.
[52] Toussirot E,Binda D,Gueugnon C,et al. Adiponectin in autoimmune diseases[J]. Current Med Chem,2012,19(32):5474-5480.
[53] Kochetkova EA,Nevsorova VA,Ugay LG,et al. Issues of adipokine regulation in idiopathic pulmonary arterial hypertension and systemic osteopenia[J]. Kardiologiia,2018,2:17-23.
[54] Kochetkova EA,Ugai LG,Maistrovskaia YV,et al. Adipokines:a possible contribution to vascular and bone remodeling in idiopathic pulmonary arterial hypertension[J]. Calcified Tissue Internat,2017,100(4):325-331.