(Circulation. 1996;93:1087-1094.)
© 1996 American Heart Association, Inc.
Articles |
From the Department of Cardiological Sciences (P.J.K., W.J.M.), St George's Hospital, London, UK; and Division of Cardiovascular Medicine (G.A.H., P.S.T., H.E.vdL., M.J.M., P.T.T., N.P.L., C.D.B., P.R.R., N.H.B., J.P.C., M.B.F.), Stanford University, Stanford, Calif.
Correspondence to Guy Haywood, MD, MRCP, or Michael Fowler, MB, MRCP, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5246.
Background There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiological importance in heart failure. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS), but there is very little information on the role of the inducible isoform.
Methods and Results We analyzed inducible NOS (iNOS) expression in ventricular myocardium taken from 11 control subjects (who had died suddenly from noncardiac causes), from 10 donor hearts before implantation, and from 51 patients with heart failure (24 with dilated cardiomyopathy [DCM], 17 with ischemic heart disease [IHD], and 10 with valvular heart disease [VHD]). Reverse transcriptionpolymerase chain reaction was used to confirm the presence of intact mRNA and to detect expression of iNOS and atrial natriuretic peptide (ANP). ANP was used as a molecular phenotypic marker of ventricular failure. iNOS was expressed in 36 of 51 biopsies (71%) from patients with heart failure and in none of the control patients (P<.0001). iNOS expression could also be detected in 50% of the donor hearts. All samples that expressed iNOS also expressed ANP. iNOS gene expression occurred in 67% of patients with DCM, 59% of patients with IHD, and 100% of patients with VHD. To determine whether iNOS protein was expressed in failing ventricles, immunohistochemistry was performed on three donor hearts and nine failing hearts with iNOS mRNA expression. Staining for iNOS was almost undetectable in the donor myocardium and in control sections, but all failing hearts showed diffuse cytoplasmic staining in cardiac myocytes. Expression of iNOS could be observed in all four chambers. Western blot analysis with the same primary antibody showed a specific positive band for iNOS protein in the heart failure specimens; minimal iNOS protein expression was seen in donor heart samples.
Conclusions iNOS expression occurs in failing human cardiac myocytes and may be involved in the pathophysiology of DCM, IHD, and VHD.
Key Words: heart failure myocardium molecular biology immunohistochemistry polymerase chain reaction
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D. Sarkar, P. Vallance, C. Amirmansour, and S. E. Harding Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides Cardiovasc Res, December 1, 2000; 48(3): 430 - 439. [Abstract] [Full Text] [PDF] |
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Y. Ishibashi, T. Shimada, T. Sakane, N. Takahashi, T. Sugamori, S. Ohhata, S.-i. Inoue, H. Katoh, K. Sano, Y. Murakami, et al. Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-Type natriuretic peptide levels in patients with congestive heart failure J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1605 - 1611. [Abstract] [Full Text] [PDF] |
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C. Badorff, B. Fichtlscherer, R. E. Rhoads, A. M. Zeiher, A. Muelsch, S. Dimmeler, and K. U. Knowlton Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through S-Nitrosylation : A Protective Mechanism Against Enteroviral Cardiomyopathy Circulation, October 31, 2000; 102(18): 2276 - 2281. [Abstract] [Full Text] [PDF] |
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D. Kalra, G. Baumgarten, Z. Dibbs, Y. Seta, N. Sivasubramanian, and D. L. Mann Nitric Oxide Provokes Tumor Necrosis Factor-{alpha} Expression in Adult Feline Myocardium Through a cGMP-Dependent Pathway Circulation, September 12, 2000; 102(11): 1302 - 1307. [Abstract] [Full Text] [PDF] |
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G. Valen, G. Paulsson, A. M. Bennet, G. K. Hansson, and J. Vaage Gene expression of inflammatory mediators in different chambers of the human heart Ann. Thorac. Surg., August 1, 2000; 70(2): 562 - 567. [Abstract] [Full Text] [PDF] |
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D. M. Weinstein, M. J. Mihm, and J. A. Bauer Cardiac Peroxynitrite Formation and Left Ventricular Dysfunction following Doxorubicin Treatment in Mice J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 396 - 401. [Abstract] [Full Text] |
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J. M. Hare, R. A. Lofthouse, G. J. Juang, L. Colman, K. M. Ricker, B. Kim, H. Senzaki, S. Cao, R. S. Tunin, and D. A. Kass Contribution of Caveolin Protein Abundance to Augmented Nitric Oxide Signaling in Conscious Dogs With Pacing-Induced Heart Failure Circ. Res., May 26, 2000; 86(10): 1085 - 1092. [Abstract] [Full Text] [PDF] |
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S. D. Prabhu, B. Chandrasekar, D. R. Murray, and G. L. Freeman {beta}-Adrenergic Blockade in Developing Heart Failure : Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling Circulation, May 2, 2000; 101(17): 2103 - 2109. [Abstract] [Full Text] [PDF] |
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T. Shinke, H. Takaoka, M. Takeuchi, K. Hata, H. Kawai, H. Okubo, Y. Kijima, T. Murata, and M. Yokoyama Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to {beta}-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy Circulation, April 25, 2000; 101(16): 1925 - 1930. [Abstract] [Full Text] [PDF] |
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F. Jung, L. A. Palmer, N. Zhou, and R. A. Johns Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes Circ. Res., February 18, 2000; 86(3): 319 - 325. [Abstract] [Full Text] [PDF] |
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T. Ide, H. Tsutsui, S. Kinugawa, N. Suematsu, S. Hayashidani, K. Ichikawa, H. Utsumi, Y. Machida, K. Egashira, and A. Takeshita Direct Evidence for Increased Hydroxyl Radicals Originating From Superoxide in the Failing Myocardium Circ. Res., February 4, 2000; 86(2): 152 - 157. [Abstract] [Full Text] [PDF] |
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M. N. Sack, R. M. Smith, and L. H. Opie Tumor necrosis factor in myocardial hypertrophy and ischaemia -- an anti-apoptotic perspective Cardiovasc Res, February 1, 2000; 45(3): 688 - 695. [Full Text] [PDF] |
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K. J. Osterziel, S. M Bode-Boger, O. Strohm, A. E Ellmer, N. Bit-Avragim, D. Hanlein, M. B Ranke, R. Dietz, and R. H Boger Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy Cardiovasc Res, January 14, 2000; 45(2): 447 - 453. [Abstract] [Full Text] [PDF] |
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L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF] |
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E. Isenovic and M. C. LaPointe Role of Ca2+-Independent Phospholipase A2 in the Regulation of Inducible Nitric Oxide Synthase in Cardiac Myocytes Hypertension, January 1, 2000; 35(1): 249 - 254. [Abstract] [Full Text] [PDF] |
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A. M Shah Inducible nitric oxide synthase and cardiovascular disease Cardiovasc Res, January 1, 2000; 45(1): 148 - 155. [Full Text] [PDF] |
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N. Kobayashi, T. Higashi, K. Hara, H. Shirataki, and H. Matsuoka Effects of imidapril on NOS expression and myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats Cardiovasc Res, December 1, 1999; 44(3): 518 - 526. [Abstract] [Full Text] [PDF] |
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B. Yang, D. F. Larson, and R. Watson Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1906 - H1913. [Abstract] [Full Text] [PDF] |
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M. A. Arstall, D. B. Sawyer, R. Fukazawa, and R. A. Kelly Cytokine-Mediated Apoptosis in Cardiac Myocytes : The Role of Inducible Nitric Oxide Synthase Induction and Peroxynitrite Generation Circ. Res., October 29, 1999; 85(9): 829 - 840. [Abstract] [Full Text] [PDF] |
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M Tendera and H Wysocki TNF-{alpha} in patients with chronic failure is not only a proinflammatory cytokine Eur. Heart J., October 2, 1999; 20(20): 1445 - 1446. [PDF] |
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M. V. Brahmajothi and D. L. Campbell Heterogeneous Basal Expression of Nitric Oxide Synthase and Superoxide Dismutase Isoforms in Mammalian Heart : Implications for Mechanisms Governing Indirect and Direct Nitric Oxide-Related Effects Circ. Res., October 1, 1999; 85(7): 575 - 587. [Abstract] [Full Text] [PDF] |
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T. de Frutos, L. S. de Miguel, M. Garcia-Duran, F. Gonzalez-Fernandez, J. A. Rodriguez-Feo, M. Monton, J. Guerra, J. Farre, S. Casado, and A. Lopez-Farre NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-alpha Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1317 - H1325. [Abstract] [Full Text] [PDF] |
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D. J. Pinsky, W. Aji, M. Szabolcs, E. S. Athan, Y. Liu, Y. M. Yang, R. P. Kline, K. E. Olson, and P. J. Cannon Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1189 - H1199. [Abstract] [Full Text] [PDF] |
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W. J Paulus and A. M Shah NO and cardiac diastolic function Cardiovasc Res, August 15, 1999; 43(3): 595 - 606. [Full Text] [PDF] |
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M. Nagashima, U. Stock, G. Nollert, J. Sperling, D. Shum-Tim, S. Hatsuoka, and J. E. Mayer Jr Effects of cyanosis and hypothermic circulatory arrest on lung function in neonatal lambs Ann. Thorac. Surg., August 1, 1999; 68(2): 499 - 504. [Abstract] [Full Text] [PDF] |
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