Role of Oxidative Stress and Autophagy in Thoracic Aortic Aneurysms

Irace, Francesco Giosuè; Cammisotto, Vittoria; Valenti, Valentina; Forte, Maurizio; Schirone, Leonardo; Bartimoccia, Simona; Iaccarino, Alessandra; Peruzzi, Mariangela; Schiavon, Sonia; Morelli, Andrea; Marullo, Antonino G. M.; Miraldi, Fabio; Nocella, Cristina; Paulis, Ruggero De; Benedetto, Umberto; Greco, Ernesto; Biondi‐Zoccai, Giuseppe; Sciarretta, Sebastiano; Carnevale, Roberto; Frati, Giacomo

doi:10.1016/j.jacbts.2021.08.002

Cited by 16 publications

(11 citation statements)

References 28 publications

(33 reference statements)

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“…94 In the aortic tissue of TAA patients, lower levels of autophagy could be observed. 95 After VSMC-specific knockdown of the autophagy-related gene Atg5, an increased incidence of AA in mice with increased ER stress levels and upregulated inflammation was observed, and these phenomena were also verified in human AA tissues. 96 The above section describes the role and mechanism of VSMCs in AA, such as phenotype switching, cell death, autophagy, and ECM regulation.…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 81%

The mechanism and therapy of aortic aneurysms

Gao

Cao

et al. 2023

Sig Transduct Target Ther

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Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.

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Section: Vascular Smooth Muscle Cellsmentioning

confidence: 81%

The mechanism and therapy of aortic aneurysms

Gao

Cao

et al. 2023

Sig Transduct Target Ther

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“…Cellular ROS and labile iron increase ferroptosis in a dose- and time-dependent manner (Sui et al 2018 ). Oxidative stress is closely related to the pathophysiology of cardiovascular disease, including hypertension, atherosclerosis, aortic aneurysm, and vascular restenosis (Chan and Chan 2014 ; Kattoor et al 2017 ; Irace et al 2021 ; Vendrov et al 2006 ). ROS is a regulator of VSMC phenotypic switching (Clempus and Griendling 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice

Zhang

Bei

Huang

et al. 2022

Mol Med

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Background Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear. Methods The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments. Results Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-l-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs. Conclusions Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.

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“…In contrast, when challenged, EC become activated, pro-thrombotic and adhesive, and can also influence VSMC phenotype and exacerbate TAA, although mechanisms remain to be fully explained [ 26 ]. Low NO availability may impair signaling between EC and VSMC and is associated with an inflammatory response to adverse stimuli [ 27 , 28 , 29 , 30 ]. There are conflicting data regarding EC proliferation and migration in TAA.…”

Section: Cell Function In Normal and Aneurysmal Aortamentioning

confidence: 99%

Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions

Dong

Malecki

Robertson

et al. 2023

IJMS

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Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.

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Role of Oxidative Stress and Autophagy in Thoracic Aortic Aneurysms

Abstract: Visual Abstract

Cited by 16 publications

References 28 publications

The mechanism and therapy of aortic aneurysms

The mechanism and therapy of aortic aneurysms

Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice

Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions

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