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

Abstract

The involvement of highly reactive oxygen-derived free radicals (ROS) in the genesis and progression of various cardiovascular diseases, including arrhythmias, aortic dilatation, aortic dissection, left ventricular hypertrophy, coronary arterial disease and congestive heart failure, is well-established. It has also been suggested that ROS may play a role in aortic aneurysm formation in patients with Marfan’s syndrome (MFS). This syndrome is a multisystem disorder with manifestations including cardiovascular, skeletal, pulmonary and ocular systems, however, aortic aneurysm and dissection are still the most life-threatening manifestations of MFS. In this review, we will concentrate on the impact of oxidative stress on aneurysm formation in patients with MFS as well as on possible beneficial effects of some agents with antioxidant properties. Mechanisms responsible for oxidative stress in the MFS model involve a decreased expression of superoxide dismutase (SOD) as well as enhanced expression of NAD(P)H oxidase, inducible nitric oxide synthase (iNOS) and xanthine oxidase. The results of studies have indicated that reactive oxygen species may be involved in smooth muscle cell phenotype switching and apoptosis as well as matrix metalloproteinase activation, resulting in extracellular matrix (ECM) remodeling. The progression of the thoracic aortic aneurysm was suggested to be associated with markedly impaired aortic contractile function and decreased nitric oxide-mediated endothelial-dependent relaxation.

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

“…In the cardiovascular system, ROS are involved, among other dysfunctions, in the development of aortic abdominal aneurysms (AAA) through the regulation of inflammation induction, matrix metalloproteinases (MMPs) expression, vascular smooth muscle cell (VSMC) apoptosis and phenotypic changes and modifying extracellular matrix properties [4][5][6][7][8][9][10] , but are much less understood in thoracic aortic aneurysm (TAA) of genetic origin, such as in MFS and Loeys-Dietz syndrome (LDS) 11 . We and others have shown that ROS production is increased in MFS [12][13][14][15][16][17][18] , although their sources and impact on the formation and/or progression in either human or murine MFS aortic aneurysms is still not well established 19,20 . We reported the involvement of upregulated NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (NOX4) both in human and mouse MFS aortic samples and cultured VSMC [17].…”

“…However, the impact of ROS on thoracic aortic aneurysm (TAA) of genetic origin, such as in MFS and Loeys-Dietz syndrome (LDS), is less known 11 . We and others have previously shown that ROS production is increased in MFS [12][13][14][15][16][17][18] , although the specific generators of ROS and their respective impact on the formation and/or progression in either human or murine MFS aortic aneurysms is still poorly understood 19,20 . We reported the involvement of upregulated NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (NOX4) both in human and mouse MFS aortic samples and cultured VSMCs 17 .…”

Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

“…Damaging the structure of the endothelium enables lipids, primarily low-density lipoproteins (LDL) and lipoprotein (a) (Lp(a)) to penetrate the aortic leaflets, and can also trigger the migration of inflammatory cells within [ 17 , 18 ]. Plaque-like lesions consisting of LDL, Lp(a), and inflammatory cells form in the subendothelial region contributing to the production of reactive oxygen species (ROS) that promotes the oxidation of LDL and vascular dysfunction [ 17 , 19 , 20 ]. The persistent inflammatory process enables valvular interstitial cells (VICs) to attain an osteogenic phenotype resulting in the production of microcalcifications and leaflet mineralization [ 7 , 11 ].…”

“…Over the course of CAVD progression under the influence of periostin, TNF-α, IL-1β, TGF-β1, RANKL, and excessive strain matrix metalloproteinases (MMPs) (especially MMP-1/9/12) and their tissue inhibitors (TIMPs) are secreted by ECs, myofibroblasts, macrophages, and T cells modulating collagen turnover in fibrotic aortic leaflets [ 6 , 19 , 37 , 88 , 89 , 90 ]. In addition to MMPs and TIMPs, cathepsins S/K/V [ 10 , 11 , 66 , 84 ] and elastin-degrading proteases enhance the remodeling and degradation of the vascular extracellular matrix (VECM) [ 89 , 91 ].…”

“…The major antioxidant effects are mediated by SIRT1, Nrf2, and the ER (estrogen receptor) reducing arterial calcification by downregulating RUNX2, osteocalcin, and ALP [ 83 , 126 , 127 , 128 ]. In addition to having an anti-inflammatory impact, precursors of resveratrol (palmitoylethanolamide, polydatin) significantly reduced the expression of VCAM, ICAM-1, TNF- α, IL-1, alleviating vascular injury [ 19 , 49 , 129 , 130 , 131 , 132 ].…”