The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications

Abstract

Despite the elucidation of the pathways behind the development of aortic stenosis (AS), there remains no effective medical treatment to slow or reverse its progress. Instead, the gold standard of care in severe or symptomatic AS is replacement of the aortic valve. Oxidative stress is implicated, both directly as well as indirectly, in lipid infiltration, inflammation and fibro-calcification, all of which are key processes underlying the pathophysiology of degenerative AS. This culminates in the breakdown of the extracellular matrix, differentiation of the valvular interstitial cells into an osteogenic phenotype, and finally, calcium deposition as well as thickening of the aortic valve. Oxidative stress is thus a promising and potential therapeutic target for the treatment of AS. Several studies focusing on the mitigation of oxidative stress in the context of AS have shown some success in animal and in vitro models, however similar benefits have yet to be seen in clinical trials. Statin therapy, once thought to be the key to the treatment of AS, has yielded disappointing results, however newer lipid lowering therapies may hold some promise. Other potential therapies, such as manipulation of microRNAs, blockade of the renin-angiotensin-aldosterone system and the use of dipeptidylpeptidase-4 inhibitors will also be reviewed.

Multiomics coupled with vibrational spectroscopy identify early mechanisms of experimental aortic valve stenosis

“…Reduced pyroglutamic acid is also linked to ROS, since it is derived from oxidized glutathione. In this context, we evaluated the relative expression of ROS-related genes 35,36 (Fig. 7a).…”

Lysyl Oxidase in Ectopic Cardiovascular Calcification: Role of Oxidative Stress

“…Initially viewed as a passive degenerative process, CVC is indeed a complex and well-orchestrated phenomenon entailing inflammation, the osteogenic transdifferentiation of resident vascular smooth muscle cells (VSMCs) and valve interstitial cells (VICs), extracellular matrix (ECM) remodeling, and oxidative stress [6]. Certainly, increasing evidence supports the concept that the excessive production of reactive oxygen species (ROS) plays an active role in CVC, fostering the osteochondrogenic differentiation of VSMCs and VICs, while favoring inflammation [7][8][9]. Further, ECM remodeling is a hallmark of CVC and a critical player in biomineralization [10,11].…”

Albumin Thiolation and Oxidative Stress Status in Patients with Aortic Valve Stenosis

“…Recent findings have highlighted an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the onset and progression of valvular disease, which can contribute to the differentiation of valve interstitial cells into myofibroblasts and osteoblasts [6]. Indeed, oxidative stress, a condition derived from an imbalance between ROS production and ROS degradation, is involved in several pathological processes, such as inflammation, lipid infiltration, and calcification, all aspects that participate in cardiovascular disease, including aortic valve disease [7]. In addition, ROS induce the oxidation of several molecules, redox gene overexpression, and DNA fragmentation, all of which contribute to myocardial cell damage [8].…”