Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
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DOI：
10.1093/cvr/cvz290
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发表时间：
2020-10-01
影响因子：
10.8
通讯作者：
Mitchell JA
中科院分区：
文献类型：
--
作者：
Kirkby NS;Raouf J;Ahmetaj-Shala B;Liu B;Mazi SI;Edin ML;Chambers MG;Korotkova M;Wang X;Wahli W;Zeldin DC;Nüsing R;Zhou Y;Jakobsson PJ;Mitchell JA
非甾体抗炎药（NSAID）均抑制环氧合酶（考克斯）-2，其引起的心血管副作用阻碍了靶向野牡丹素治疗炎症和癌症的新药的开发。微粒体前列腺素E合成酶-1（mPGES-1）抑制剂在NSAID竞技场中具有疗效，但其心血管安全性尚不清楚。我们以前的工作确定了不对称二甲基精氨酸（ADMA），一种内皮型一氧化氮合酶抑制剂，作为与阻断考克斯-2相关的心血管毒性的潜在生物标志物。在这里，我们使用药理学工具和转基因小鼠描绘mPGES-1和考克斯-2在ADMA的调节。抑制考克斯-2而非mPGES-1缺失导致血浆ADMA水平升高。mPGES-1缺失而非考克斯-2抑制导致血浆前列环素水平升高。这些差异可通过肾脏中考克斯-2和mPGES-1的明显区室化来解释。前列腺素合酶/受体敲除小鼠的数据显示，考克斯-2/ADMA轴受前列环素受体（IP和PPARβ/δ）和抑制性PGE 2受体EP 4控制，而不是其他PGE 2受体。这些数据表明，mPGES-1的抑制使肾考克斯-2/ADMA通路不受影响，并从机制上确定了考克斯-2如何调节ADMA。
Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.
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DOI：
10.1161/atvbaha.112.247726
发表时间：
2012-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Caplin B;Leiper J
通讯作者：
Leiper J
影响因子：
3.7
作者：
Kirkby NS;Lundberg MH;Wright WR;Warner TD;Paul-Clark MJ;Mitchell JA
通讯作者：
Mitchell JA
影响因子：
10.8
作者：
Gitlin, Jonathan M.;Loftin, Charles D.
通讯作者：
Loftin, Charles D.
影响因子：
4.8
作者：
Mitchell, Jane A.;Lucas, Ruth;Warner, Timothy D.
通讯作者：
Warner, Timothy D.
DOI：
10.1073/pnas.90.24.11693
发表时间：
1993-12-15
影响因子：
11.1
作者：
MITCHELL, JA;AKARASEREENONT, P;VANE, JR
通讯作者：
VANE, JR