二甲基精氨酸二甲氨基水解酶 2 调节一氧化氮合成和血液动力学，并决定多微生物脓毒症的结局。
Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis.
机构信息
From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
出版信息
Arterioscler Thromb Vasc Biol. 2015 Jun;35(6):1382-92. doi: 10.1161/ATVBAHA.115.305278. Epub 2015 Apr 9.
OBJECTIVE
Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl-L-arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl-L-arginine is dimethylarginine dimethylaminohydrolase (DDAH). The first isoform dimethylarginine dimethylaminohydrolase 1 has previously been shown to be an important regulator of methylarginines in both health and disease. This study explores for the first time the role of endogenous dimethylarginine dimethylaminohydrolase 2 in regulating cardiovascular physiology and also determines the functional impact of dimethylarginine dimethylaminohydrolase 2 deletion on outcome and immune function in sepsis.
APPROACH AND RESULTS
Mice, globally deficient in Ddah2, were compared with their wild-type littermates to determine the physiological role of Ddah2 using in vivo and ex vivo assessments of vascular function. We show that global knockout of Ddah2 results in elevated blood pressure during periods of activity (mean [SEM], 118.5 [1.3] versus 112.7 [1.1] mm Hg; P=0.025) and changes in vascular responsiveness mediated by changes in methylarginine concentration, mean myocardial tissue asymmetric dimethylarginine (SEM) was 0.89 (0.06) versus 0.67 (0.05) μmol/L (P=0.02) and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome (120-hour survival was 12% in Ddah2 knockouts versus 53% in wild-type animals; P<0.001). Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals.
CONCLUSIONS
Ddah2 has a regulatory role both in normal physiology and in determining outcome of severe polymicrobial sepsis. Elucidation of this role identifies a mechanism for the observed relationship between Ddah2 polymorphisms, cardiovascular disease, and outcome in sepsis.
目的
一氧化氮是许多生理和病理生理过程的关键。内源性 2 甲基精氨酸、不对称二甲基精氨酸（ADMA）和单甲基-L-精氨酸调节一氧化氮的产生。专门代谢不对称二甲基精氨酸和单甲基-L-精氨酸的酶是二甲基精氨酸二甲氨基水解酶（DDAH）。先前已经表明，第一同工型二甲基精氨酸二甲氨基水解酶 1 是健康和疾病中甲基精氨酸的重要调节剂。本研究首次探讨了内源性二甲基精氨酸二甲氨基水解酶 2 在调节心血管生理学中的作用，并确定了二甲基精氨酸二甲氨基水解酶 2 缺失对脓毒症结局和免疫功能的功能影响。
方法和结果
使用体内和离体评估血管功能，将缺乏 Ddah2 的小鼠与它们的野生型同窝仔鼠进行比较，以确定 Ddah2 的生理作用。我们表明，Ddah2 的全局敲除导致活动期间血压升高（平均值[SEM]，118.5[1.3]与 112.7[1.1]毫米汞柱；P=0.025）和血管反应性的变化介导的甲基精氨酸浓度的变化，心肌组织中不对称二甲基精氨酸的平均（SEM）为 0.89（0.06）与 0.67（0.05）μmol/L（P=0.02）和系统一氧化氮浓度。在严重多微生物脓毒症模型中，Ddah2 敲除影响结局（Ddah2 敲除动物的 120 小时存活率为 12%，而野生型动物为 53%；P<0.001）。单核细胞特异性缺失 Ddah2 导致严重程度与全身性缺失动物相似。
结论
Ddah2 在正常生理学和确定严重多微生物脓毒症结局中都具有调节作用。阐明这一作用确定了观察到的 Ddah2 多态性、心血管疾病和脓毒症结局之间的关系的机制。
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