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.

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Background-Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels.However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (LdlrϪ/Ϫ/Apob ) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease. Methods and Results-After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85Ϯ0.04 to 0.70Ϯ0.04 mm (meanϮSE; PϽ0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation. Conclusions-Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis. Key Words: aortic valve stenosis Ⅲ calcification Ⅲ free radicals Ⅲ hypercholesterolemia Ⅲ valves R eplacement of the aortic valve is the primary treatment for patients with symptomatic calcific aortic valve stenosis and is the second-most-common thoracic surgery procedure in the United States. 1 Risk factors for the development of aortic valve stenosis are similar to those of atherosclerosis and include older age, 2 male sex, hypertension, smoking, diabetes mellitus, 1,2 and hypercholesterolemia. 2 Stenotic aortic valves resemble atherosclerotic lesions pathologically and contain calcium, 3 high levels of matrix-remodeling enzymes, 4 -6 reduced endothelial nitric oxide synthase levels, 7 and increased oxidative stress. 8 -10 Both stenotic valves and atherosclerotic lesions contain a subpopulation of cells with osteoblast-like activity, [11][12][13][14] suggesting that deposition of calcium in these lesions is an active process. Editorial see p 2653 Clinical Perspective on p 2701Reducing plasma cholesterol levels in humans and experimental animals slows the progression and/or reduces the size of atherosclerotic lesions, 15,16 reduces oxidative stress, 17 and improves nitric oxide bioavailability, 15,18 ...

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