The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms

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.

Keywords: inflammation; matrix metalloproteinases; myeloperoxidase; oxidative stress; thoracic aortic aneurysm.

Figure 1

Proposed relationship between inflammation, MPO production, and worsening TAA phenotype. The development of a TAA leads to an increased inflammatory infiltrate and increased MPO-derived oxidant generation, which directly damage the ECM, activate MMPs, both directly and through ERK1/2 signaling, and inactivate tissue inhibitors of metalloproteinases (TIMPs). These oxidants also precipitate endothelial dysfunction and vascular smooth muscle cell (VSMC) phenotypic switching. Taken together, these changes disrupt aortic wall homeostasis, resulting in a repeating cycle of more severe TAA development.