Abstract
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 A2 (TXA2) 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 (p = 0.02), an increase in oleic acid (OA), TGFβ1, tumor necrosis factor alpha (TNFα), prostaglandin E2 (PGE2) (p < 0.05), and COXs activity (p = 0.002) was found. The expressions of phospholipase A2 (PLA2), cytochrome P450 (CYP450 4A), 5-lipoxygenase (5-LOX), COX2 and TXA2R (p < 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-PG1α) 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 PLA2, COX2/TXA2R, CYP450 4A, and 5-LOX which leads to a greater synthesis of PGE2 than of 6-keto-PGF1α, 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.
Highlights
The Marfan syndrome (MFS) is a pleiotropic genetic disease with involvement of the cardiovascular, ocular and skeletal system with a very wide clinical variability
We showed that OS in MFS is associated with alterations in enzymes that employ glutathione, leading to increased chronic inflammation (Zúñiga-Muñoz et al, 2017).the vasomotor function in Marfan thoracic aorta is associated with an imbalance in the synthesis of thromboxane A2 (TXA2) and prostacyclin derived from the differential protein expression of cyclooxygenase (COXs) isoforms (Chung et al, 2007b)
Our results suggest that, in the aorta the MFS patients, there exists an imbalance in the synthesis of the prostaglandins given by an increase of prostaglandin E2 (PGE2), TXA2 and decrease of 6-keto-PG1α which result from the altered metabolism of arachidonic acid (AA) through the rate limiting enzymes COX1 and cyclooxygenase 2 (COX2)
Summary
The Marfan syndrome (MFS) is a pleiotropic genetic disease with involvement of the cardiovascular, ocular and skeletal system with a very wide clinical variability. The alteration in the expression of this protein can lead to destruction of the assembly of normal microfibrils and the production of abnormal elastic fibers and, as a consequence it leads to changes in elasticity in the aortic tissue causing growth and instability (Granata et al, 2016). This damage results in structural variations within the same arterial vessel with inherent heterogeneity in its content, thickness and cellular composition (Soto et al, 2014). The blockage of TGFβ1 release through anti-TGFβ1 antibodies reduces aortic root dilation in studies in mice (Cohn et al, 2007)
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