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  • br Introduction Localized degenerative and progressive enlar

    2019-11-06


    Introduction Localized, degenerative and progressive enlargement of the aortic diameter involves all layers of the vessel wall may ultimately rupture creating a catastrophic cardiovascular event [1,2]. An aneurysm may be located in the thoracic or abdominal aortic wall with different clinical appearance and prognosis [3]. Hypertension, age [4], smoking [5,6] and genetic history [7,8] are the most common risk factors for this disease, which is more prevalent among men [9]. Despite modern diagnostic tools, open surgery or endovascular repair at late stages are the current treatments [10].
    AAA pathophysiology The arterial wall comprises three layers: tunica intima, media and adventitia. Specific cell types characterize each layer: the innermost layer, tunica intima, mostly consists of endothelial cells (EC). The media layer is dominated by smooth muscle cells (SMC), elastin- and collagen-fibers, although in large arteries such as the calcitonin gene related peptide and its major branches, the media wall has a high content of elastic fibers. Finally, the adventitia is mainly composed of connective tissue [11,12]. The molecular and cellular mechanisms that trigger aneurysm formation are not fully understood. However, in the AAA wall multiple signs of a degenerative process are observed involving degradation of extracellular matrix proteins (i.e. elastin and collagen by metalloproteinases, MMP); chronic and transmural inflammation accompanied by accumulation of neutrophils, lymphocytes and macrophages; degradation of connective tissue within the tunica media and adventitia; SMC apoptosis in the media; loss of medial and adventitial elastin contributing to increased risk of rupture [[13], [14], [15]] (Fig. 1). It has been reported that AAA environment contributes to the development of oxidative stress, since during the inflammatory process immune cells can generate large amounts of reactive oxygen species (ROS) such as O2− and H2O2 while SMC and EC form O2− [16]. ROS, in turn, regulate chemotactic cytokines (i.e. IL-8 and monocyte chemoattractant peptide-1) and intercellular adhesion molecule-1 (ICAM-1), inhibits plasminogen activator inhibitor-1 contributing to the increase of proteolysis and degradation of the ECM [17]. Cytokines can promote a vicious cycle since they themselves can induce the production of ROS. Interactions between T lymphocytes and macrophages, these cells and other immune cells also play a role in aneurysm formation [18]. For example, the CD69 antigen expressed on T-lymphocytes is responsible for lymphocytes interactions with monocytes/macrophages leading to the production cytokines (IL-1), MMPs and other matrix degrading proteases [19,20]. Thus, indicating that aorta function is based on cell-cell interactions, communication with ECM, immune cell invasion and continuous tissue remodeling. Moreover, biomechanical wall-stress also promotes aneurysm formation and progression [21,22].
    The leukotrienes Leukotrienes (LT) are powerful inflammatory lipid mediators synthesized from arachidonic acid via the 5-lipoxygenase (5-LOX) pathway, comprising the enzymes cytosolic phospholipase A2 (cPLA2), 5-LOX, 5-lipoxygenase activating protein (FLAP), coactosin-like protein (CLP), which together generate the unstable epoxide intermediate LTA4. The two down-stream enzymes, LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S) further converts LTA4 into LTB4 and LTC4, respectively. The tripeptide moiety of LTC4 may be further cleaved to generate LTD4 and LTE4 and together these three molecules comprise the cysteinyl-leukotrienes (cys-LT) (Fig. 2). While LTB4 is one of the most powerful chemotactic agent for leukocytes known to date, the cys-LT are potent smooth muscle contracting agents [23]. The LTs exert their actions through two sets of GPCR, BLT1 and BLT2 for LTB4 and CysLT1, CysLT2, and GPR99 for cys-LT [24]. Due to their strong bioactions, the leukotrienes are implicated in the pathophysiology of several chronic inflammatory diseases, especially asthma and rhinitis [25]. The LTs are also implicated in cardiovascular diseases such as atherosclerosis, myocardial infarction and recently, AAA [[26], [27], [28], [29], [30], [31], [32], [33]].