Abstract
Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.
Highlights
Aneurysms, defined as the permanent dilation of an artery to a diameter 1.5 times greater than normal size, predispose to the potentially fatal events of dissection or rupture
The role of inflammation and oxidative stress is well established in the pathogenesis of abdominal aortic aneurysms (AAA) [14]; it is more controversial in genetically triggered thoracic aortic aneurysms (TAAs), which are traditionally classified as non-inflammatory lesions [15]
Some forms of TAA have been clearly associated with a known primary pathogenic gene variant, such as FBN1 in Marfan syndrome (MFS), while the causative variants/s remain unknown for other forms of familial TAA, and Bicuspid aortic valve (BAV)
Summary
Aneurysms, defined as the permanent dilation of an artery to a diameter 1.5 times greater than normal size, predispose to the potentially fatal events of dissection or rupture. Identified genes affect diverse protein systems, including extracellular matrix (ECM) regulation (FBN1, FBN2, COL3A1), vascular smooth muscle cell (VSMC) contractile apparatus (MYH11, ACTA2), and transforming growth factor-beta (TGF-β) signaling (TGFB2, TGFBR1, SMAD3). Each of these protein systems has an essential role in maintaining the structural integrity of the aortic wall. The role of inflammation and oxidative stress is well established in the pathogenesis of AAA [14]; it is more controversial in genetically triggered TAAs, which are traditionally classified as non-inflammatory lesions [15]. This review will explore the emerging evidence of inflammation and oxidative stress in the pathogenesis of genetically triggered TAAs, with a focus on links between inflammation, myeloperoxidase (MPO) production, and its consequences in the vasculature, to examine how these factors may contribute to TAA disease progression
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