Targeted deletions of cyclooxygenase-2 and atherogenesis in mice.
Targeted deletions of cyclooxygenase-2 and atherogenesis in mice.
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DOI：
10.1161/circulationaha.109.910687
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发表时间：
2010-06-22
期刊：
影响因子：
37.8
通讯作者：
FitzGerald GA
中科院分区：
文献类型：
--
作者：
Hui Y;Ricciotti E;Crichton I;Yu Z;Wang D;Stubbe J;Wang M;Puré E;FitzGerald GA
尽管血管环氧化酶（考克斯）-2的主要产物前列环素（PGI 2）抑制动脉粥样硬化形成，但在动脉粥样硬化小鼠模型中抑制和缺失考克斯-2产生了相互矛盾的结果。Floxed小鼠用于解析巨噬细胞（Mac）和T细胞（TC）中考克斯-2对动脉粥样硬化形成的不同细胞贡献。使用LysMCre小鼠获得Mac考克斯-2（MacKO）的缺失，并且完全抑制脂多糖（LPS）刺激的Mac前列腺素（PG）形成，并且LPS诱发的系统性PG生物合成降低约30%。LPS刺激的考克斯-2的表达在从MacKO分离的多形核白细胞（PMN）中被抑制，但在对照小鼠的PMN上清液中甚至没有检测到PG形成。当Mac科斯与高脂血症LdlR科斯杂交时，动脉粥样硬化减弱。Mac考克斯-2的缺失似乎消除了对表达血管细胞粘附分子和α-平滑肌肌动蛋白和波形蛋白的病变非白细胞（CD 45和CD 11 b阴性）血管细胞中考克斯-2表达的限制，预示着PG谱的改变和随后的动脉粥样硬化保护作用。考克斯-2的基础表达在TC中是最小的，但是使用CD 4Cre产生TC敲除（TCKO）抑制了抗CD 3 ε对其的适度上调。然而，PGs的生物合成、淋巴器官中的TC组成和LDLR科斯中的动脉粥样硬化形成在TCKO中没有改变。Mac考克斯-2主要是血栓烷A2和PGE 2的来源，促进动脉粥样硬化形成并抑制病变细胞的酶表达，提示血管平滑肌细胞是动脉粥样硬化保护性PGI 2的主要来源。TC考克斯-2对小鼠TC的形成和功能以及动脉粥样硬化的形成均无明显影响。
While the dominant product of vascular cyclooxygenase (COX)-2, prostacyclin (PGI2), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages (Mac) and T cells (TC) to atherogenesis. Deletion of Mac COX-2 (MacKO) was attained using LysMCre mice and suppressed completely lipopolysaccharide (LPS) stimulated Mac prostaglandin (PG) formation and LPS evoked systemic PG biosynthesis by ∼ 30%. LPS stimulated COX-2 expression was suppressed in polymorphonuclear leucocytes (PMN) isolated from MacKOs, but PG formation was not even detected in PMN supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic LdlR KOs. Deletion of Mac COX-2 appeared to remove a restraint on COX-2 expression in lesional non-leukocyte (CD45 and CD11b negative) vascular cells that express vascular cell adhesion molecule and variably, α-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts (TCKOs) depressed its modest upregulation by anti-CD3ε. However, biosynthesis of PGs, TC composition in lymphatic organs and atherogenesis in LDLR KOs were unaltered in TCKOs. Mac COX-2, primarily a source of thromboxane A2 and PGE2, promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective PGI2. TC COX-2 does not influence detectably TC development or function nor atherogenesis in mice.