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 |
|
Related Articles
-
Oxidation, Inflammation, and Aortic Valve Calcification: Peroxide Paves an Osteogenic Path
- Dwight A. Towler
J. Am. Coll. Cardiol. 2008 52: 851-854.
[Full Text]
[PDF]
-
Inside This Issue of JACC
J. Am. Coll. Cardiol. 2008 52: A31-A32.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
R. Li, D. Mittelstein, J. Lee, K. Fang, R. Majumdar, Y. Tintut, L. L. Demer, and T. K. Hsiai
A dynamic model of calcific nodule destabilization in response to monocyte- and oxidized lipid-induced matrix metalloproteinases
Am J Physiol Cell Physiol,
February 15, 2012;
302(4):
C658 - C665.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. M. Rajamannan, F. J. Evans, E. Aikawa, K. J. Grande-Allen, L. L. Demer, D. D. Heistad, C. A. Simmons, K. S. Masters, P. Mathieu, K. D. O'Brien, et al.
Calcific Aortic Valve Disease: Not Simply a Degenerative Process: A Review and Agenda for Research From the National Heart and Lung and Blood Institute Aortic Stenosis Working Group * Executive Summary: Calcific Aortic Valve Disease - 2011 Update
Circulation,
October 18, 2011;
124(16):
1783 - 1791.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. I. Bostrom, N. M. Rajamannan, and D. A. Towler
The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens
Circ. Res.,
August 19, 2011;
109(5):
564 - 577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-S. Shao, O. L. Sierra, R. Cohen, R. P. Mecham, A. Kovacs, J. Wang, K. Distelhorst, A. Behrmann, L. R. Halstead, and D. A. Towler
Vascular Calcification and Aortic Fibrosis: A Bifunctional Role for Osteopontin in Diabetic Arteriosclerosis
Arterioscler Thromb Vasc Biol,
August 1, 2011;
31(8):
1821 - 1833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Joghetaei, P. Akhyari, B. H. Rauch, P. Cullen, A. Lichtenberg, M. Rudelius, J. Pelisek, and R. Schmidt
Extracellular matrix metalloproteinase inducer (CD147) and membrane type 1-matrix metalloproteinase are expressed on tissue macrophages in calcific aortic stenosis and induce transmigration in an artificial valve model
J. Thorac. Cardiovasc. Surg.,
July 1, 2011;
142(1):
191 - 198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-H. Chen and C. A. Simmons
Cell-Matrix Interactions in the Pathobiology of Calcific Aortic Valve Disease: Critical Roles for Matricellular, Matricrine, and Matrix Mechanics Cues
Circ. Res.,
June 10, 2011;
108(12):
1510 - 1524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Miller, R. M. Weiss, and D. D. Heistad
Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms
Circ. Res.,
May 27, 2011;
108(11):
1392 - 1412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Towler
Vascular Calcification: It's All the RAGE!
Arterioscler Thromb Vasc Biol,
February 1, 2011;
31(2):
237 - 239.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Miller, R. M. Weiss, K. M. Serrano, L. E. Castaneda, R. M. Brooks, K. Zimmerman, and D. D. Heistad
Evidence for Active Regulation of Pro-Osteogenic Signaling in Advanced Aortic Valve Disease
Arterioscler Thromb Vasc Biol,
December 1, 2010;
30(12):
2482 - 2486.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Gielen, G. Schuler, and V. Adams
Cardiovascular Effects of Exercise Training: Molecular Mechanisms
Circulation,
September 21, 2010;
122(12):
1221 - 1238.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. S. Speidl, G. Cimmino, B. Ibanez, S. Elmariah, R. Hutter, M. J. Garcia, V. Fuster, M. E. Goldman, and J. J. Badimon
Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model
Eur. Heart J.,
August 2, 2010;
31(16):
2049 - 2057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Hjortnaes, J. Butcher, J.-L. Figueiredo, M. Riccio, R. H. Kohler, K. M. Kozloff, R. Weissleder, and E. Aikawa
Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation
Eur. Heart J.,
August 2, 2010;
31(16):
1975 - 1984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-L. Cheng, J.-S. Shao, L. R. Halstead, K. Distelhorst, O. Sierra, and D. A. Towler
Activation of Vascular Smooth Muscle Parathyroid Hormone Receptor Inhibits Wnt/{beta}-Catenin Signaling and Aortic Fibrosis in Diabetic Arteriosclerosis
Circ. Res.,
July 23, 2010;
107(2):
271 - 282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Rahimtoola
The Year in Valvular Heart Disease
J. Am. Coll. Cardiol.,
April 20, 2010;
55(16):
1729 - 1742.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-S. Shao, S.-L. Cheng, J. Sadhu, and D. A. Towler
Inflammation and the Osteogenic Regulation of Vascular Calcification: A Review and Perspective
Hypertension,
March 1, 2010;
55(3):
579 - 592.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Matsumoto, V. Adams, S. Jacob, N. Mangner, G. Schuler, and A. Linke
Regular Exercise Training Prevents Aortic Valve Disease in Low-Density Lipoprotein-Receptor-Deficient Mice
Circulation,
February 16, 2010;
121(6):
759 - 767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. M. Rajamannan
Mechanisms of aortic valve calcification: the LDL-density-radius theory: a translation from cell signaling to physiology
Am J Physiol Heart Circ Physiol,
January 1, 2010;
298(1):
H5 - H15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Almeida, E. Ambrogini, L. Han, S. C. Manolagas, and R. L. Jilka
Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-{gamma} Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton
J. Biol. Chem.,
October 2, 2009;
284(40):
27438 - 27448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Pena-Silva, J. D. Miller, Y. Chu, and D. D. Heistad
Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves
Am J Physiol Heart Circ Physiol,
October 1, 2009;
297(4):
H1354 - H1360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Owens and C. M. Otto
Is it Time for a New Paradigm in Calcific Aortic Valve Disease?
J. Am. Coll. Cardiol. Img.,
August 1, 2009;
2(8):
928 - 930.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Koleganova, G. Piecha, E. Ritz, P. Schirmacher, A. Muller, H.-P. Meyer, and M.-L. Gross
Arterial calcification in patients with chronic kidney disease
Nephrol. Dial. Transplant.,
August 1, 2009;
24(8):
2488 - 2496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Miller, R. M. Weiss, K. M. Serrano, R. M. Brooks II, C. J. Berry, K. Zimmerman, S. G. Young, and D. D. Heistad
Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice
Circulation,
May 26, 2009;
119(20):
2693 - 2701.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Parolari, C. Loardi, L. Mussoni, L. Cavallotti, M. Camera, P. Biglioli, E. Tremoli, and F. Alamanni
Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention
Eur J Cardiothorac Surg,
March 1, 2009;
35(3):
493 - 504.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, J. J. Bax, G. K. Feld, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, S. M. Narayan, D. J. Sahn, et al.
Highlights of the Year in JACC 2008
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
373 - 398.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Towler
Oxidation, Inflammation, and Aortic Valve Calcification: Peroxide Paves an Osteogenic Path
J. Am. Coll. Cardiol.,
September 2, 2008;
52(10):
851 - 854.
[Full Text]
[PDF]
|
|
|
|
