Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities

Abstract

Background: The primary objective of this review was to explore the contribution of oxidative stress to the pathogenesis of genetically-triggered thoracic aortic aneurysm (TAA). Genetically-triggered TAAs manifest substantial variability in onset, progression, and risk of aortic dissection, posing a significant clinical management challenge. There is a need for non-invasive biomarkers that predict the natural course of TAA and therapeutics that prevent aneurysm progression. Methods: An online systematic search was conducted within PubMed, MEDLINE, Scopus and ScienceDirect databases using keywords including: oxidative stress, ROS, nitrosative stress, genetically triggered thoracic aortic aneurysm, aortic dilatation, aortic dissection, Marfan syndrome, Bicuspid Aortic Valve, familial TAAD, Loeys Dietz syndrome, and Ehlers Danlos syndrome. Results: There is extensive evidence of oxidative stress and ROS imbalance in genetically triggered TAA. Sources of ROS imbalance are variable but include dysregulation of redox mediators leading to either insufficient ROS removal or increased ROS production. Therapeutic exploitation of redox mediators is being explored in other cardiovascular conditions, with potential application to TAA warranting further investigation. Conclusion: Oxidative stress occurs in genetically triggered TAA, but the precise contribution of ROS to pathogenesis remains incompletely understood. Further research is required to define causative pathological relationships in order to develop therapeutic options.

Oxidative Stress-Related Susceptibility to Aneurysm in Marfan’s Syndrome

“…Moreover, they suggested that in MFS, the intensity of oxidative stress could be a marker of the clinical severity and the number of organs/systems affected. Oxidative stress has been demonstrated to disrupt mechano-signaling within the aortic wall, stimulate pathological switching of VSMCs phenotype and their apoptosis and enhance the expression of ECM-degrading matrix metalloproteinases (MMP) [ 78 , 79 ]. All the aforementioned processes induce aortic wall degeneration and thoracic aortic aneurysm formation [ 80 ].…”

“…Interestingly, they found that higher production of ROS was limited solely to the aneurysmal site [ 82 ]. Moreover, the restoration of normal redox homeostasis with the use of ROS inhibition or antioxidant supplementation was found to ameliorate vasomotor function and decrease aneurysmal dilatation [ 79 ]. According to many studies, mechanisms responsible for oxidative stress in an MFS mouse model involve decreased expression of SOD as well enhanced expression of NAD(P)H oxidase, inducible nitric oxide synthase (iNOS) and xanthine oxidase [ 77 ].…”

Oxidative Stress Inside the Pathogenesis of Ascending Aorta Aneurysms: A Clearer Vision for Identifying Promising Biomarkers and Therapeutic Targets

“…Moreover, it has been also demonstrated that NOX, xanthine oxidase (XO), myeloperoxidase, (MPO), lipoxygenase (LOX), cyclooxygenase (COX), uncoupled endothelial nitric oxide synthase (eNOS), other amine oxidases, and non-enzymic sources including electron leakage from the mitochondrial electron transport chain, result altered in expression and function in patients with AsAA(see Table 2) [40].…”

“…In contrast of CTGF activity and the enzymes abovementioned, and similarly to the actions mediated of Sirt3 [41], diverse intracellular enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), have the role of maintaining the ROS levels in a precise balance for reducing the eventual increase during the pathogenesis of diseases, such as AsAA [amply quoted in 42]. But evidence has recently reported that an impaired functioning of these enzymes, as well as a mitochondrial dysfunction, characterize patients affected by AsAA, as elegantly summarized by Portelli and co-workers [40]. Particular attention has been also given to Prdxs, antioxidant enzymes involved in the regulation of OS and H2O2-mediated intracellular signaling, by other researcher groups.…”

Allopurinol Blocks Aortic Aneurysm in a Mouse Model of Marfan Syndrome via Reducing Aortic Oxidative Stress

“…ROS are also involved in the development of aortic aneurysms through the regulation of inflammation induction, matrix metalloproteinase (MMP) expression, vascular smooth muscle cell (VSMC) apoptosis, and phenotypic changes, as well as modifying extracellular matrix properties (4). The role of local redox stress (often simplified to oxidative stress) in the pathogenesis of aortic abdominal aneurysm is well documented in humans and murine models (5–10), but much less understood in thoracic aortic aneurysm (TAA) of genetic origin, such as in MFS and Loeys-Dietz syndrome (LDS) (11).…”