AGXT2與ADMA代謝及心腦血管疾病的研究進展

呼曉雷,周繼朋,陳小平

(1.中南大學湘雅醫院臨床藥理研究所，湖南 長沙 410008； 2.分子靶標新藥研究協同創新中心，湖南 長沙 410078；3.中南大學臨床藥理研究所，遺傳藥理湖南省重點實驗室，湖南 長沙 410078)

AGXT2與ADMA代謝及心腦血管疾病的研究進展

呼曉雷1,2,3,周繼朋1,2,3,陳小平1,2,3

(1.中南大學湘雅醫院臨床藥理研究所，湖南 長沙 410008； 2.分子靶標新藥研究協同創新中心，湖南 長沙 410078；3.中南大學臨床藥理研究所，遺傳藥理湖南省重點實驗室，湖南 長沙 410078)

心腦血管疾病嚴重威脅人類健康，有效預防和治療心腦血管疾病是當代醫學研究的重點。非對稱性二甲基精氨酸(asymmetric dimethylarginine，ADMA)和對稱性二甲基精氨酸(symmetric dimethylarginine，SDMA)是心腦血管疾病或心腦血管事件獨立的預測因子。丙氨酸-乙醛酸轉氨酶2(alanine-glyoxylate aminotransferase 2，AGXT2)是內源性ADMA的水解酶之一，其表達缺失或活性降低可影響體內ADMA的水平，而AGXT2的多個單核苷酸多態性與體內SDMA的水平明顯相關。深入研究AGXT2在心腦血管疾病發生發展中的作用對以AGXT2為靶點開發新型心腦血管保護藥物具有重要意義。該文就AGXT2參與ADMA的代謝及其與心腦血管疾病的最新研究進展進行綜述。

ADMA；SDMA；AGXT2；二甲基精氨酸二甲胺水解酶；單核苷酸多態性；心腦血管疾病

隨著社會經濟的發展和生活方式的改變，心腦血管疾病的患病人數逐年攀升[1]。由于我國人口結構老齡化程度持續加重，心腦血管疾病的發病形勢已經非常嚴峻，心腦血管疾病模型的開發研究也日益受到重視[2-3]。據2013年中國心臟大會《中國心血管病報告》顯示，我國目前約1/5的成年人患有心腦血管疾病，且近5年來，心腦血管疾病死亡人數居各種死因之首。心腦血管疾病已經成為我國乃至全球面臨的重大公共衛生問題之一，深入探究心腦血管疾病的發病機制、提高心腦血管疾病的防治水平和改善心腦血管疾病患者的預后刻不容緩。

1 二甲基精氨酸(dimethylarginine，DMA)與心腦血管疾病

氣體分子一氧化氮(NO) 具有強大的舒血管功能，可促進內皮細胞的增殖和遷移，抑制脂多糖誘導的內皮細胞凋亡、抑制血小板聚集及其與內皮細胞的黏附，并可在血管受損時抑制血管的畸形發展，在維持血管內皮功能和心腦血管系統穩態中起重要作用[4-5]。動脈粥樣硬化是心力衰竭和中風等多種心腦血管疾病的病理基礎，而內皮功能的紊亂則是動脈粥樣硬化的早期表現。人體內NO由L-精氨酸在NO合酶(nitric oxide synthase，NOS)的催化下生成，當NOS活性受到抑制時，NO的生成減少，血管內皮功能發生紊亂，進而導致動脈粥樣硬化等一系列的心腦血管疾病的發生發展[6-7]。

二甲基精氨酸是體內含精氨酸的蛋白質被蛋白精氨酸甲基轉移酶(protein-arginine methyltransferase，PRMT)甲基化的產物，分為非對稱性二甲基精氨酸(asymmetric dimethylarginine，ADMA)和對稱性二甲基精氨酸(symmetric dimethylarginine，SDMA)兩種(Fig 1)，均在調節體內NO的合成中發揮重要作用。

Fig 1 Synthetic and metabolic pathways of DMA

*CAT: Cationic amino acid transporters.

1.1 ADMA與心腦血管疾病ADMA具有與L-精氨酸相似的結構，可競爭結合NOS并抑制其活性，減少NO的生成，進而引起炎癥反應和內皮功能紊亂，促進多種心腦血管疾病的發生與發展[8]。有學者測定了151例平均年齡為57歲無糖尿病并發癥的冠心病患者血漿ADMA的含量，并對冠狀動脈的狹窄程度進行分級，發現冠脈狹窄程度較重的患者血漿中ADMA的水平高于狹窄程度較輕的患者，且ADMA水平與Sullivan評分呈正相關[9]。隨機雙盲安慰劑對照試驗結果表明，低劑量ADMA可升高健康志愿者的血壓[10]。未經治療的原發性高血壓患者血漿中ADMA水平也明顯升高，且ADMA與原發性高血壓患者內皮功能紊亂相關[11]。Sonmez等[12]也發現了類似的現象。除高血壓、冠心病以外，心力衰竭患者血漿中ADMA水平也較健康對照人群明顯升高[13]。研究表明，慢性心衰患者血漿 ADMA 水平與紐約心臟協會(NYHA)心功能分級和血漿N端-B型利鈉肽的前體(NT-proBNP)密切相關[14]，而后者是心衰的一個重要診斷和預后指標[15]。此外，ADMA還與參與心律失常[16]、心肌梗死[17]和高膽固醇血癥[18]等多種心腦血管疾病的發生發展。血漿ADMA水平升高已成為多種心腦血管疾病及其并發癥心腦血管事件的獨立預測因子。

1.2 SDMA與心腦血管疾病SDMA雖然不抑制NOS的活性，但卻可與介導L-精氨酸跨膜轉運的陽離子轉運體hCAT-2B競爭性結合，抑制細胞攝取L-精氨酸，從源頭間接抑制NO的合成[19]。Bode-Boger等[20]首次發現SDMA與腎小球濾過率及冠心病的嚴重程度相關。Schulze等[21]對394例急性缺血性腦卒中患者進行了長達7.5年的隨訪，發現SDMA是急性缺血性腦卒中患者全因死亡的獨立預測因子，風險比為2.41。此外，有報道表明，SDMA也可預測冠狀動脈疾病及其主要不良心腦血管事件的發生風險[22]。對健康志愿者進行的研究發現，血漿ADMA和SDMA水平呈明顯的正相關，兩者水平升高的個體5年觀測期內發生心腦血管疾病的風險比分別達3.86和7.91[23]。可見，SDMA和ADMA都可作為心腦血管疾病及心腦血管事件的預測因子[24]。

2 DMA的體內代謝

人體內ADMA和SDMA的代謝途徑存在差別，SDMA主要以原型形式經腎臟直接排泄，而ADMA則主要經過一系列的酶促反應代謝消除[25]。二甲基精氨酸二甲胺水解酶(dimethylarginine dimethylaminohydrolase，DDAH)是體內ADMA的主要水解酶，可將ADMA代謝為瓜氨酸和二甲胺[26]。DDAH有兩種亞型，分別是DDAH1和DDAH2。DDAH1主要表達在中樞神經系統、肝臟、腎臟、肺和骨骼肌等組織和器官的血管內皮細胞中，DDAH2則主要在心臟、腎臟、內皮細胞和血管平滑肌細胞等組織和細胞中表達[27]。研究證實，DDAH1是體內代謝滅活ADMA的主要酶[28-29]。我們的前期研究發現，人類DDAH1存在3個不同的轉錄本，而在原代培養的人臍靜脈內皮細胞中，只有DDAH1-V1轉錄本的表達水平與ADMA代謝活性相關[30]。此外，近年來的研究發現，位于線粒體的丙氨酸-乙醛酸轉氨酶2(alanine-glyoxylate aminotransferase 2, AGXT2)也參與ADMA的體內代謝，該酶以ADMA作為氨基供體，催化其分解為α-酮-δ-(N，N-二甲基胍)戊酸[α-keto-δ-(N, N-dimethyl-guanidino) valeric acid，DMGV][31-32]，在短期內降低體內ADMA水平中發揮重要的作用[33](Fig 1)。

3 AGXT2與心腦血管疾病的臨床研究

3.1 AGXT2與ADMA代謝AGXT是一種依賴磷酸吡哆醛(pyridoxal 5-phosphate)的氨基轉移酶，以L-丙氨酸為氨基供體，不可逆地將乙醛酸鹽轉化成甘氨酸[34]。多種哺乳動物肝臟或腎臟中均能檢測到AGXT的表達[35]。AGXT存在兩種亞型，分別是AGXT1和AGXT2(Fig 2)，兩者在細胞內分布、結構和功能上均存在明顯的差異。AGXT1主要分布于過氧化物酶體，兼具丙氨酸-乙醛酸和絲氨酸-丙酮酸兩種氨基轉移酶的活性[36]，其基因突變導致活性降低或表達缺失時可引發Ⅰ型原發性高草酸尿癥(primary hyperoxaluria，PH1)[37-38]。AGXT2經核糖體翻譯過后運送至線粒體中發揮生理效應，不具有絲氨酸-丙酮酸轉氨酶的活性，但參與ADMA的代謝。

Rodionov等[31]發現過表達人AGXT2的小鼠肝臟和血漿中ADMA水平均明顯降低，從而間接促進血管內皮細胞NO的合成。Caplin等[39]的研究發現，AGXT2基因敲除小鼠血漿ADMA的水平明顯升高，而其代謝產物DMGV的血漿濃度水平則明顯降低。AGXT2的底物β-氨基異丁酸(β-aminoisobutyrate，BAIB)可與ADMA競爭AGXT2，并在有丙酮酸鹽(pyruvate)的情況下被AGXT2代謝為氧代丙酸甲酯(2-methyl-3-oxopropanoate )和丙氨酸(alanine)[40]。通過微型泵向C57/BL6小鼠腹腔內灌注BAIB 后發現，小鼠血漿ADMA和SDMA的水平均明顯升高，而DMGV的水平明顯下降[41]。這些研究均提示，AGXT2在ADMA代謝中的重要作用。

Fig 2 Expression and function of AGXT*PLP：Pyridoxal 5′-phosphate

3.2 AGXT2基因多態性與心腦血管疾病的臨床相關研究由于AGXT2在內源性活性物質ADMA和BAIB等代謝中的重要作用，近年來有關AGXT2基因遺傳變異的臨床相關性的研究也相繼展開。Suhre等[40]對人體尿液中59種代謝產物進行的全基因組關聯研究(genome wide association study，GWAS)發現，AGXT2的非同義多態性rs37369(Val140Ile)與尿液BAIB水平間呈很強的關聯(P=3.17×10-75)。Rhee等[42]隨后發現AGXT2 rs37370位點與血漿BAIB的水平間存在非常明顯的關聯性。也有GWAS研究發現rs37369位點T等位基因可升高舒張壓的水平(P=0.0052)[39]。此外，有學者發現，AGXT2基因位點rs37369和rs16899974多態性與血清SDMA水及心率變異性(heart rate variability，HRV)明顯相關，rs37369多態性同時還與ADMA/SDMA的比值相關聯[43]。在一項納入了394例中風患者進行的研究發現，AGXT2基因的rs28305、rs40200和rs37369多態位點均與體內SDMA的水平相關聯性，其中rs40200多態性可在一定程度上預測中風患者的預后[44]。我們的前期研究發現，rs37369多態性與中國漢族吸煙人群冠心病的發病風險，該位點GG基因型(Val140Val)可升高吸煙且同時伴有糖尿病的個體冠心病的發病風險，其機制可能與吸煙狀態下血漿中ADMA水平升高有關[45]。

Tab 1 Genetic polymorphism of AGXT2 in clinical researches

4 總結與展望

大量研究業已證實，ADMA能競爭性抑制NOS的活性，而SDMA也可通過干擾L-精氨酸的攝取從而間接抑制NO的生成。隨著對AGXT2在ADMA和SDMA代謝中作用認識的深入，AGXT2表達缺失或者活性降低可能是導致心腦血管疾病患者體內ADMA水平改變和內皮功能紊亂的重要機制[46-49]。近年來已發現，AGXT2基因的多個單核苷酸多態性位點與ADMA和SDMA及其他內源性物質的代謝存在明顯的關聯(Tab 1)，提示AGXT2基因位點可能存在導致其表達或酶活性發生改變的功能性遺傳變異，目前關于這些位點多態性的功能研究相對較少，且這些多態位點與心腦血管疾病易感性關系的研究也鮮見報道。進一步深入探究AGXT2及其遺傳變異在心腦血管發病機制中的作用，可為開發靶點為AGXT2的新型心腦血管保護藥物奠定基礎，進而改善我國心腦血管疾病高發病率、高患病率、高死亡率的現狀。

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Role of AGXT2 in ADMA metabolism and the development of cardiovascular and cerebrovascular diseases

HU Xiao-lei1,2,3, ZHOU Ji-peng1,2,3,CHEN Xiao-ping1,2,3

(1.DeptofClinicalPharmacology,XiangyaHospital,CentralSouthUniversity,Changsha410008,China;2.HunanProvinceCooperativeInnovationCenterforMolecularTargetNewDrugStudy,Changsha410078,China;3.InstituteofClinicalPharmacology,CentralSouthUniversity,HunanKeyLaboratoryofPharmacogenetics,Changsha410078,China)

Cardiovascular and cerebrovascular diseases have become a great health threat. Increasing evidence has shown that both asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) play important and independent roles in the development of cardiovascular and cerebrovascular diseases as well as in the prediction of cardiovascular and cerebrovascular events. Alanine-glyoxylate aminotransferase 2 (AGXT2) is recently observed to be involved in ADMA metabolism. Deficiency in the expression and activity of AGXT2 may thus play a role in the development of cardiovascular and cerebrovascular diseases by affecting ADMA levelsinvivo. Several single-nucleotide polymorphisms at AGXT2 locus are observed to be associated with plasma SDMA level. This review summarizes recent advances in AGXT2 and its role in ADMA metabolism and the clinical relevance.

ADMA; SDMA; AGXT2; dimethylarginine dimethylaminohydrolase; SNP; cardiovascular and cerebrovascular diseases

時間：2015-4-15 15:44 網絡出版地址：http://www.cnki.net/kcms/detail/34.1086.R.20150415.1545.003.html

2015-02-24,

2015-03-27

國家自然科學基金資助項目(No 81170091)

呼曉雷(1989-)，男，碩士生，研究方向：心腦血管疾病的藥物基因組學，Tel：0731-84805380，E-mail：huxiaolei66@126.com； 陳小平(1974-)，女，博士，研究員，博士生導師，研究方向：藥物基因組學，通訊作者，Tel：0731-84805380， E-mail：chenxp74@hotmail.com

10.3969/j.issn.1001-1978.2015.05.003

A

1001-1978(2015)05-0601-05

R-05；R540.1；R977.4；R977.3