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CLINICAL RESEARCH: VALVULAR HEART DISEASE

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

Jordan D. Miller, PhD^_*,_*, Yi Chu, PhD^_*,, Robert M. Brooks, BS^_*, Wayne E. Richenbacher, MD, Ricardo Peña-Silva, MD^_*, and Donald D. Heistad, MD^_*,,

^_* Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa
Department of Cardiothoracic Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
Veterans Affairs Medical Center, Iowa City, Iowa

Manuscript received November 12, 2007; revised manuscript received May 1, 2008, accepted May 27, 2008.

^_* Reprint requests and correspondence: Dr. Jordan D. Miller, University of Iowa, Department of Internal Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242 (Email: jordan-miller{at}uiowa.edu).

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.

Key Words: aortic valve • calcification • oxidative stress • stenosis

Abbreviations and Acronyms   DHE = dihydroethidine   L-NAME = nitro-L-arginine methyl ester   mRNA = messenger ribonucleic acid   NADPH = nicotinamide adenine dinucleotide phosphate   NOS = nitric oxide synthase   SOD = superoxide dismutase

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