Dysregulation of Antioxidant Mechanisms Contributes to Increased Oxidative Stress in Calcific Aortic Valvular Stenosis in Humans

Abstract

Objectives The aim of this study was to determine whether oxidative stress is increased in calcified, stenotic aortic valves and to examine mechanisms that might contribute to increased oxidative stress. Background Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear. Methods Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide (H2O2) (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve. Results In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions. Conclusions This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

“…6 Although several risk factors are shared between atherosclerotic diseases and CAVD, discrepancies in their pathogenesis have also been identified. [8][9][10] These results highlight the necessity of investigating prognostic factors for incidence and progression of CAVD in Asian populations.…”

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

“…Oxidative stress has been shown to participate in the development of CAVD (Miller et al 2008;Kennedy et al 2009;Li and Förstermann 2013) and be associated with local hemodynamic changes (Richards et al 2013). NOS3, commonly known as eNOS, has long been known for its protective effects against aortic valve inflammation and calcification (Clapp et al 2004;Kennedy et al 2009).…”

“…NOS3, commonly known as eNOS, has long been known for its protective effects against aortic valve inflammation and calcification (Clapp et al 2004;Kennedy et al 2009). Low expression of eNOS can reduce the cellular NO level, thus contributing to oxidative stress and facilitating eNOS uncoupling, which will, in turn, increase the generation of reactive oxygen species (ROS) and promote further oxidative damage to the endothelium (Miller et al 2008;Li and Förstermann 2013).…”

Discovery of an Experimental Model of Unicuspid Aortic Valve

“…Myofibroblasts may then transdifferentiate further into osteoblast‐like cells, which produce matrix calcification 24. Similar processes occur in diseased human valves, in which α‐SMA and calcification colocalize 25. In aortic valves from Velvet mice, α‐SMA and calcification are minimal, even when significant valve dysfunction is present.…”