Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins.
Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins.
复制标题
内膜平滑肌细胞是抗炎 CYP450 衍生的氧脂质的来源，但不是传感器。
DOI：
10.1016/j.bbrc.2015.06.012
复制
发表时间：
2015
影响因子：
3.1
通讯作者：
Bishop-Bailey,David
中科院分区：
文献类型：
--
作者：
Thomson,Scott;Edin,MatthewL;Lih,FredB;Davies,Michael;Yaqoob,MuhammadM;Hammock,BruceD;Gilroy,Derek;Zeldin,DarrylC;Bishop-Bailey,David
血管病理与形态学上不同的血管平滑肌细胞的存在和表达的变化相关。特别地，在猪和啮齿动物的复杂的人血管病变和疾病模型中，通常发现在培养物中表现出稳定的上皮样或菱形表型的内膜平滑肌细胞（iSMC）大量存在，并且可能代表独特的发育血管平滑肌细胞表型的重新出现。CYP 450-氧脂素-可溶性环氧化物水解酶（sEH）途径目前在靶向心血管疾病方面引起极大兴趣。sEH抑制剂限制动物模型中高血压、糖尿病、动脉粥样硬化和动脉瘤形成的发展。我们研究了CYP 450-oxlipin-sEH途径酶及其代谢产物在大鼠主动脉分离的成对内膜（iSMC）和中膜（mSMC）细胞中的表达。与mSMC相比，iSMC基础释放的环氧氧化脂CYP 450产物显著更大量，来自二十碳五烯酸>二十二碳六烯酸>花生四烯酸>亚油酸，并表达更高水平的CYP 2C 12、CYP 2B 1，但不表达CYP 2 J mRNA。当用促炎性TLR 4配体LPS刺激时，iSMC中环氧-氧化脂素的产生没有很大变化。与此相反，LPS诱导mSMC中的环氧-氧化脂质产物并诱导CYP 2 J 4。iSMC和mSMC表达sEH，其将初级环氧-氧脂代谢为其二羟基-对应物。sEH抑制剂TPPU或AUDA可抑制LPS诱导的mSMC中NFκB活化和iNOS诱导，但对iSMC中NFκB核定位或诱导型一氧化氮合酶无影响;添加真正的环氧-氧化脂质可部分重现这种影响。iSMC是抗炎环氧-氧脂素的丰富来源，但不是其传感器。含有高水平iSMC的复杂病变可能对sEH抑制剂的保护作用更具抗性。
Vascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-oxylipins to their dihydroxy-counterparts. The sEH inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors.