TRPV1通道作为高血压防治新靶点研究进展
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摘要
起初发现于大脑和各类感觉神经元中的瞬时受体电位香草酸亚型1(Transient Receptor Potential Vanilloid Subtype 1, TRPV1)是主要的镇痛药物开发靶点之一。近年来,大量生理及病理学研究发现其在血管内皮细胞、血管平滑肌细胞和血管周神经细胞中呈高水平表达并参与了多种血管功能调节。因此,TRPV1在调控血管功能中发挥的作用已引起重视,以TRPV1或其作用通路为靶点开发抗高血压药物具有潜在的临床应用价值。现就近年来TRPV1通道与抗高血压机制有关的研究进展,和以其为靶点进行药物开发时的关注点作一综述,供相关药物研发者参考。
The Transient Receptor Potential Vanilloid Subtype 1(TRPV1), which was first identified in the brain and various sensory neurons, is one of the major targets in the development of analgesic drugs. Accumulating physiological and pathological studies in recent years have demonstrated that the TRPV1 is highly expressed in the vascular endothlial cells, vascular smooth muscle cells and perivascular nerve cells, and it also participates in the regulations of a variety of vascular functions. Therefore, the role of TRPV1 in regulating vascular functions has attracted lots of attention, so the development of antihypertensive drugs with TRPV1 or its pathway as the target might be valuable in clinical practice. In this paper, the recent research progress of the anti-hypertensive mechanisms of TRPV1 and the focus on the development of the drugs targeting at TRPV1 were briefly reviewed so as to provide the references for the relevant drug research and development.
The Transient Receptor Potential Vanilloid Subtype 1(TRPV1), which was first identified in the brain and various sensory neurons, is one of the major targets in the development of analgesic drugs. Accumulating physiological and pathological studies in recent years have demonstrated that the TRPV1 is highly expressed in the vascular endothlial cells, vascular smooth muscle cells and perivascular nerve cells, and it also participates in the regulations of a variety of vascular functions. Therefore, the role of TRPV1 in regulating vascular functions has attracted lots of attention, so the development of antihypertensive drugs with TRPV1 or its pathway as the target might be valuable in clinical practice. In this paper, the recent research progress of the anti-hypertensive mechanisms of TRPV1 and the focus on the development of the drugs targeting at TRPV1 were briefly reviewed so as to provide the references for the relevant drug research and development.
引文
[1]Wong N D,Franklin S S.Reducing the Burden of Hypertension:China's Long March Ahead[J].Jama Intern Med,2016,176(4):532-533.
[2]田军,郝博济.抗高血压药物靶标及剂型的研发进展[J].中国药房,2013(9):852-855.
[3]Zheng,J.Molecular Mechanism of TRP Channels[J].Compr Physiol,2013,3(1):221-242.
[4]Cosens DJ,Manning A.Abnormal Electroretinogram from a Drosophila Mutant[J].Nature,1969,224(5216):285-287.
[5]Liao M,Cao E,Julius D,et al.Structure of The TRPV1 Ion Channel Determined by Electron Cryo-microscopy[J].Nature,2013,504(7478):107-112.
[6]Cao E,Liao M,Cheng Y,et al.TRPV1 Structures in Distinct Conformations Reveal Mechanisms of Activation[J]Nature,2013,504(7478):113.
[7]Caterina M J,Schumacher M A,Tominaga M,et al.The Capsaicin Receptor:a Heat-activated Ion Channel in the Pain Pathway[J].Nature,1997,389(6653):816-824.
[8]Chen J,Ajp H,Finsterbusch M,et al.Endogenously Generated Arachidonate-derived Ligands for TRPV1 Induce Cardiac Protection in Sepsis[J].FASEB J,2018:fj201701303R.
[9]Yang F,Ma L,Cao X,et al.Divalent Cations Activate TRPV1 Through Promoting Conformational Change of the Extracellular Region[J].J Gen Physiol,2014,143(1):91-103.
[10]Bae C,Anselmi C,Kalia J,et al.Structural Insights Into the Mechanism of Activation of the TRPV1 Channel by a Membrane-bound Tarantula Toxin[J].Elife,2016,5(5):533-535.
[11]Luo X J,Peng J,Liab Y J.Recent Advances in the Study on Capsaicinoids and Capsinoids[J].Eur J Pharmacol,2011,650(1):1-7.
[12]Peng J,Li Y J.The Vanilloid Receptor TRPV1:Role in Cardiovascular and Gastrointestinal Protection[J].Eur J Pharmacol,2010,627(1-3):1-7.
[13]Tóth A,Czikora A,Pásztor E T,et al.Vanilloid Receptor-1(TRPV1)Expression and Function in the Vasculature of the Rat[J].J Histochem Cytochem,2014,62(2):129-144.
[14]赵秀丽,陈捷,崔艳丽,等.中国14省市高血压现状的流行病学研究[J].中华医学杂志,2006,86(16):1148-1152.
[15]徐兴森.激活TRPV1预防动脉粥样硬化及脑卒中的机制研究[D].重庆:第三军医大学,2012.
[16]杨大春,马双陶,马丽群,等.辣椒素抑制血管紧张素Ⅱ介导的血管收缩[J].中华高血压杂志,2009(5):416-420.
[17]Yu SQ,Ma S,Wang DH,et al.Activation of TRPV1 Prevents Salt-induced Kidney Damage and Hypertension After Renal Ischemia-reperfusion Injury in Rats[J].Kidney Blood Press Res,2018,43(4):1285-1296.
[18]Akabori H,Yamamoto H,Tsuchihashi H,et al.Transient Receptor Potential Vanilloid 1 Antagonist,Capsazepine,Improves Survival in a Rat Hemorrhagic Shock Model[J].Ann Surg,2007,245(6):964-970.
[19]Li X,Hou J,Du J,et al.Potential Protective Mechanism in the Cardiac Microvascular Injury[J].Hypertension,2018,72(1):116-127.
[20]Zhang MJ,Yin YW,Li BH,et al.The Role of TRPV1 in Improving VSMC Function and Attenuating Hypertension[J].Prog Biophys Mol Biol,2015,117(2/3):212-216.
[21]Chen Y S,Lu M J,Huang H S,et al.Mechanosensitive Transient Receptor Potential Vanilloid Type 1 Channels Contribute to Vascular Remodeling of Rat Fistula Veins[J].J Vasc Surg,2010,52(5):1310-1320.
[22]Ching L C,Chen C Y,Su K H,et al.Implication of AMP-activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-mediated Activation of Endothelial Nitric Oxide Synthase[J].Mol Med,2012,18(5):805-815.
[23]Zhang M J,Liu Y,Hu Z C,et al.TRPV1 Attenuates Intracranial Arteriole Remodeling Through Inhibiting VSMC Phenotypic Modulation in Hypertension[J].Histochem Cell Biol,2017,147(4):511-521.
[24]Plane F,Holland M,Waldron G J,et al.Evidence that Anandamide and EDHF Act via Different Mechanisms in Rat Isolated Mesenteric Arteries[J].Br J Pharmacol,2010,121(8):1509-1511.
[25]Zygmunt P M,Petersson J,Andersson D A,et al Vanilloid Receptors on Sensory Nerves Mediate the Vasodilator Action of Anandamide[J].Nature,1999,400(6743):452-457.
[26]Scotland R S,Chauhan S,Davis C,et al.Vanilloid Receptor TRPV1,Sensory C-Fibers,and Vascular Autoregulation A Novel Mechanism Involved in Myogenic Constriction[J].Circ Res,2004,95(10):1027-1034.[2 7]W e n H,?s t m a n J,B u b b K J,e t a l.2 0-Hydroxyeicosatetraenoic Acid(20-HETE)is a Novel Activator of Transient Receptor Potential Vanilloid 1(TRPV1)Channel[J].J Biol Chem,2012,287(17):13868-13876.
[28]Bubb K J,Wen H,Panayiotou C M,et al.Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-hydroxyeicosatetraenoic Acid-induced Vasoactivity:Role for Protein Kinase A[J].Hypertension,2013,62(2):426-433.
[29]Wang Y,Kaminski N E,Wang D H.Endocannabinoid Regulates Blood Pressure via Activation of the Transient Receptor Potential Vanilloid Type 1 in Wistar Rats Fed a High-Salt Diet[J].J Pharmacol Exp Ther,2007,321(2):763-769.
[30]Jara-Oseguera A,Simon S A,Rosenbaum T.TRPV1:On the Road to Pain Relief[J].Curr Mol Pharmacol,2008,1(3):255-269.
[31]Li BH,Yin YW,Liu Y,et al.TRPV1 Activation Impedes Foam Cell Formation by Inducing Autophagy in OxLDL-Treated Vascular Smooth Muscle Cells[J].Cell Death Dis,2014,5(4):e1182.
[32]Hofmann N A,Barth S,Waldeckweiermair M,et al.TRPV1 Mediates Cellular Uptake of Anandamide and Thus Promotes Endothelial Cell Proliferation and NetworkFormation[J].Biol Open,2014,3(12):1164-1172.
[33]Hoi PM,Visintin C,Okuyama M,et al.Vascular Pharmacology of a Novel Cannabinoid-like Compound,3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)Benzamide(VSN16)in the Rat[J].Br J Pharmacol,2007,152(5):751-764.
[34]Mccarty MF,Dinicolantonio JJ,O'Keefe JH.Capsaicin May Have Important Potential for Promoting Vascular and Metabolic Health[J].Open Heart,2015,2(1):e000262.
[35]Lejeune M P G M,Kovacs E M R,Westerterpplantenga MS.Effect of Capsaicin on Substrate Oxidation and Weight Maintenance After Modest Body-weight Loss in Human Subjects[J].Br J Nutr,2003,90(3):651-659.
[36]Robbins N,Koch SE,Rubinstein J.Targeting TRPV1 and TRPV2 for Potential Therapeutic Interventions in Cardiovascular Disease[J].Transl Res,2013,161(6):469-476.
[2]田军,郝博济.抗高血压药物靶标及剂型的研发进展[J].中国药房,2013(9):852-855.
[3]Zheng,J.Molecular Mechanism of TRP Channels[J].Compr Physiol,2013,3(1):221-242.
[4]Cosens DJ,Manning A.Abnormal Electroretinogram from a Drosophila Mutant[J].Nature,1969,224(5216):285-287.
[5]Liao M,Cao E,Julius D,et al.Structure of The TRPV1 Ion Channel Determined by Electron Cryo-microscopy[J].Nature,2013,504(7478):107-112.
[6]Cao E,Liao M,Cheng Y,et al.TRPV1 Structures in Distinct Conformations Reveal Mechanisms of Activation[J]Nature,2013,504(7478):113.
[7]Caterina M J,Schumacher M A,Tominaga M,et al.The Capsaicin Receptor:a Heat-activated Ion Channel in the Pain Pathway[J].Nature,1997,389(6653):816-824.
[8]Chen J,Ajp H,Finsterbusch M,et al.Endogenously Generated Arachidonate-derived Ligands for TRPV1 Induce Cardiac Protection in Sepsis[J].FASEB J,2018:fj201701303R.
[9]Yang F,Ma L,Cao X,et al.Divalent Cations Activate TRPV1 Through Promoting Conformational Change of the Extracellular Region[J].J Gen Physiol,2014,143(1):91-103.
[10]Bae C,Anselmi C,Kalia J,et al.Structural Insights Into the Mechanism of Activation of the TRPV1 Channel by a Membrane-bound Tarantula Toxin[J].Elife,2016,5(5):533-535.
[11]Luo X J,Peng J,Liab Y J.Recent Advances in the Study on Capsaicinoids and Capsinoids[J].Eur J Pharmacol,2011,650(1):1-7.
[12]Peng J,Li Y J.The Vanilloid Receptor TRPV1:Role in Cardiovascular and Gastrointestinal Protection[J].Eur J Pharmacol,2010,627(1-3):1-7.
[13]Tóth A,Czikora A,Pásztor E T,et al.Vanilloid Receptor-1(TRPV1)Expression and Function in the Vasculature of the Rat[J].J Histochem Cytochem,2014,62(2):129-144.
[14]赵秀丽,陈捷,崔艳丽,等.中国14省市高血压现状的流行病学研究[J].中华医学杂志,2006,86(16):1148-1152.
[15]徐兴森.激活TRPV1预防动脉粥样硬化及脑卒中的机制研究[D].重庆:第三军医大学,2012.
[16]杨大春,马双陶,马丽群,等.辣椒素抑制血管紧张素Ⅱ介导的血管收缩[J].中华高血压杂志,2009(5):416-420.
[17]Yu SQ,Ma S,Wang DH,et al.Activation of TRPV1 Prevents Salt-induced Kidney Damage and Hypertension After Renal Ischemia-reperfusion Injury in Rats[J].Kidney Blood Press Res,2018,43(4):1285-1296.
[18]Akabori H,Yamamoto H,Tsuchihashi H,et al.Transient Receptor Potential Vanilloid 1 Antagonist,Capsazepine,Improves Survival in a Rat Hemorrhagic Shock Model[J].Ann Surg,2007,245(6):964-970.
[19]Li X,Hou J,Du J,et al.Potential Protective Mechanism in the Cardiac Microvascular Injury[J].Hypertension,2018,72(1):116-127.
[20]Zhang MJ,Yin YW,Li BH,et al.The Role of TRPV1 in Improving VSMC Function and Attenuating Hypertension[J].Prog Biophys Mol Biol,2015,117(2/3):212-216.
[21]Chen Y S,Lu M J,Huang H S,et al.Mechanosensitive Transient Receptor Potential Vanilloid Type 1 Channels Contribute to Vascular Remodeling of Rat Fistula Veins[J].J Vasc Surg,2010,52(5):1310-1320.
[22]Ching L C,Chen C Y,Su K H,et al.Implication of AMP-activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-mediated Activation of Endothelial Nitric Oxide Synthase[J].Mol Med,2012,18(5):805-815.
[23]Zhang M J,Liu Y,Hu Z C,et al.TRPV1 Attenuates Intracranial Arteriole Remodeling Through Inhibiting VSMC Phenotypic Modulation in Hypertension[J].Histochem Cell Biol,2017,147(4):511-521.
[24]Plane F,Holland M,Waldron G J,et al.Evidence that Anandamide and EDHF Act via Different Mechanisms in Rat Isolated Mesenteric Arteries[J].Br J Pharmacol,2010,121(8):1509-1511.
[25]Zygmunt P M,Petersson J,Andersson D A,et al Vanilloid Receptors on Sensory Nerves Mediate the Vasodilator Action of Anandamide[J].Nature,1999,400(6743):452-457.
[26]Scotland R S,Chauhan S,Davis C,et al.Vanilloid Receptor TRPV1,Sensory C-Fibers,and Vascular Autoregulation A Novel Mechanism Involved in Myogenic Constriction[J].Circ Res,2004,95(10):1027-1034.[2 7]W e n H,?s t m a n J,B u b b K J,e t a l.2 0-Hydroxyeicosatetraenoic Acid(20-HETE)is a Novel Activator of Transient Receptor Potential Vanilloid 1(TRPV1)Channel[J].J Biol Chem,2012,287(17):13868-13876.
[28]Bubb K J,Wen H,Panayiotou C M,et al.Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-hydroxyeicosatetraenoic Acid-induced Vasoactivity:Role for Protein Kinase A[J].Hypertension,2013,62(2):426-433.
[29]Wang Y,Kaminski N E,Wang D H.Endocannabinoid Regulates Blood Pressure via Activation of the Transient Receptor Potential Vanilloid Type 1 in Wistar Rats Fed a High-Salt Diet[J].J Pharmacol Exp Ther,2007,321(2):763-769.
[30]Jara-Oseguera A,Simon S A,Rosenbaum T.TRPV1:On the Road to Pain Relief[J].Curr Mol Pharmacol,2008,1(3):255-269.
[31]Li BH,Yin YW,Liu Y,et al.TRPV1 Activation Impedes Foam Cell Formation by Inducing Autophagy in OxLDL-Treated Vascular Smooth Muscle Cells[J].Cell Death Dis,2014,5(4):e1182.
[32]Hofmann N A,Barth S,Waldeckweiermair M,et al.TRPV1 Mediates Cellular Uptake of Anandamide and Thus Promotes Endothelial Cell Proliferation and NetworkFormation[J].Biol Open,2014,3(12):1164-1172.
[33]Hoi PM,Visintin C,Okuyama M,et al.Vascular Pharmacology of a Novel Cannabinoid-like Compound,3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)Benzamide(VSN16)in the Rat[J].Br J Pharmacol,2007,152(5):751-764.
[34]Mccarty MF,Dinicolantonio JJ,O'Keefe JH.Capsaicin May Have Important Potential for Promoting Vascular and Metabolic Health[J].Open Heart,2015,2(1):e000262.
[35]Lejeune M P G M,Kovacs E M R,Westerterpplantenga MS.Effect of Capsaicin on Substrate Oxidation and Weight Maintenance After Modest Body-weight Loss in Human Subjects[J].Br J Nutr,2003,90(3):651-659.
[36]Robbins N,Koch SE,Rubinstein J.Targeting TRPV1 and TRPV2 for Potential Therapeutic Interventions in Cardiovascular Disease[J].Transl Res,2013,161(6):469-476.