Soto María E, Guarner-Lans Verónica, Herrera-Morales Karla Y, Pérez-Torres Israel
Department of Immunology, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City, Mexico.
Department of Physiology, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City, Mexico.
Front Physiol. 2018 Feb 12;9:77. doi: 10.3389/fphys.2018.00077. eCollection 2018.
Marfan syndrome (MFS) is a pleiotropic genetic disease involving the cardiovascular system where a fibrillin-1 mutation is present. This mutation is associated with accelerated activation of transforming growth factor β (TGFβ1) which contributes to the formation of aneurysms in the root of the aorta. There is an imbalance in the synthesis of thromboxane A (TXA) and prostacyclin, that is a consequence of a differential protein expression of the isoforms of cyclooxygenases (COXs), suggesting an alteration of arachidonic acid (AA) metabolism. The aim of this study was to analyze the participation of AA metabolism associated with inflammatory factors in the dilation and dissection of the aortic aneurysm in patients with MFS. A decrease in AA ( = 0.02), an increase in oleic acid (OA), TGFβ1, tumor necrosis factor alpha (TNFα), prostaglandin E (PGE) ( < 0.05), and COXs activity ( = 0.002) was found. The expressions of phospholipase A (PLA), cytochrome P450 (CYP450 4A), 5-lipoxygenase (5-LOX), COX2 and TXA2R ( < 0.05) showed a significant increase in the aortic aneurysm of patients with MFS compared to control subjects. COX1, 6-keto-prostaglandin 1 alpha (6-keto-PG) and 8-isoprostane did not show significant changes. Histological examination of the aortas showed an increase of cystic necrosis, elastic fibers and collagen in MFS. The results suggest that there are inflammatory factors coupled to genetic factors that predispose to aortic endothelial dysfunction in the aortic tissue of patients with MFS. There is a decrease in the percentage of AA, associated with an increase of PLA, COX2/TXA2R, CYP450 4A, and 5-LOX which leads to a greater synthesis of PGE than of 6-keto-PGF, thus contributing to the formation of the aortic aneurysm. The evident loss of the homeostasis in these mechanisms confirms that there is a participation of the AA pathway in the aneurysm progression in MFS.
马凡综合征（MFS）是一种多效性遗传病，涉及存在原纤维蛋白-1突变的心血管系统。这种突变与转化生长因子β（TGFβ1）的加速激活有关，而TGFβ1的加速激活会促使主动脉根部形成动脉瘤。血栓素A（TXA）和前列环素的合成失衡，这是环氧化酶（COXs）同工型蛋白质表达差异的结果，提示花生四烯酸（AA）代谢发生改变。本研究的目的是分析与炎症因子相关的AA代谢在MFS患者主动脉瘤扩张和夹层形成中的作用。研究发现AA减少（P = 0.02）、油酸（OA）、TGFβ1、肿瘤坏死因子α（TNFα）、前列腺素E（PGE）增加（P < 0.05）以及COXs活性增加（P = 0.002）。与对照组相比，MFS患者主动脉瘤中磷脂酶A（PLA）、细胞色素P450（CYP450 4A）、5-脂氧合酶（5-LOX）、COX2和TXA2R的表达显著增加（P < 0.05）。COX1、6-酮-前列腺素1α（6-酮-PG）和8-异前列腺素未显示出显著变化。主动脉的组织学检查显示MFS患者的囊性坏死、弹性纤维和胶原增加。结果表明，在MFS患者的主动脉组织中，存在与遗传因素相关的炎症因子，这些炎症因子易导致主动脉内皮功能障碍。AA百分比降低，同时PLA、COX2/TXA2R、CYP450 4A和5-LOX增加，导致PGE的合成比6-酮-PGF更多，从而促进主动脉瘤的形成。这些机制中内稳态的明显丧失证实了AA途径参与了MFS患者动脉瘤的进展。
