Inducible Nitric Oxide Synthase (iNOS) in the Human Heart: Expression and Localization in Congestive Heart Failure

Vejlstrup, Niels; Bouloumié, Anne; Boesgaard, Søren; Andersen, Claus B.; Nielsen‐Kudsk, Jens Erik; Mortensen, Svend Aage; Kent, Jonathan; Harrison, David G.; Busse, Rudi; Aldershvile, Jan

doi:10.1006/jmcc.1998.0686

Cited by 91 publications

(55 citation statements)

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“…There is also an overproduction of nitric oxide, due to the expression of the inducible isoform of NO synthase (Fukuchi et al, 1998;Vejlstrup et al, 1998). Importantly, a recent study has suggested correlation between chronic overexpression of NO synthase and peroxynitrite generation with cardiac enlargement, conduction defects, sudden cardiac death, and, less commonly, heart failure in mice (Mungrue et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Xiao

Chen

Zsengellér

et al. 2004

J Pharmacol Exp Ther

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Oxidant stress-induced activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of various cardiovascular diseases. We have now investigated the role of PARP in the process of cardiac remodeling and heart failure in a mouse model of heart failure induced by transverse aortic constriction (banding). The catalytic activity of PARP was inhibited by the potent isoindolinone-based PARP inhibitor INO-1001 or by PARP-1 genetic deficiency. PARP inhibition prevented the pressure overload-induced decrease in cardiac contractile function, despite the pressure gradient between both carotid arteries being comparable in the two experimental groups. The development of hypertrophy, the formation of collagen in the hearts, and the mitochondrial-to-nuclear translocation of the cell death factor apoptosis-inducing factor (AIF) were attenuated by PARP inhibition. The ability of the inhibitor to block the catalytic activity of PARP was confirmed by immunohistochemical detection of poly(ADP-ribose), the product of the enzyme in the heart. Plasma levels of INO-1001, as measured at the end of the experiments, were in the concentration range sufficient to block the oxidant-mediated activation of PARP in murine cardiac myocytes in vitro. Myocardial hypertrophy and AIF translocation was also reduced in PARP-1-deficient mice undergoing aortic banding, compared with their wild-type counterparts. Overall, the current results demonstrate the importance of poly(ADP-ribos)ylation in the pathogenesis of banding-induced heart failure.Poly(ADP-ribose) polymerase (PARP)-1, a monomeric enzyme present in eukaryotes, is the major isoform of an expanding family of poly(ADP-ribosyl)ating enzymes (for review, see Virá g and Szabó, 2002). The main isoform of the family, PARP-1, primarily functions as a DNA damage sensor in the nucleus. Upon binding to damaged DNA mainly through the second zinc finger domain, PARP-1 forms homodimers and catalyzes the cleavage of NAD ϩ into nicotinamide and ADP-ribose and uses the latter to synthesize branched nucleic acid-like polymers poly(ADP-ribose) covalently attached to nuclear acceptor proteins. The biological role of PARP-1 is complex and includes the regulation of DNA repair and maintenance of genomic integrity.PARP-1 has been implicated in a variety of pathophysiological processes. PARP is an energy-consuming enzyme, which transfers ADP ribose units to nuclear proteins. As a result of this process, the intracellular nicotinamide dinucleotide (oxidized) (NAD ϩ ) and ATP levels remarkably decrease, resulting in cell dysfunction and cell death via the necrotic route (for review, see Virá g and Szabó, 2002).PARP becomes activated in response to DNA single-strand breaks, which can develop as a response to free radical and oxidant cell injury. Oxidative and nitrosative stress triggers the activation of the nuclear enzyme PARP, which contributes to the pathogenesis of various cardiovascular diseases, including myocardial infarction and ischemia-reperfusion and heart failure (for review, s...

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Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Xiao

Chen

Zsengellér

et al. 2004

J Pharmacol Exp Ther

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“…[1][2][3][4] NO has been shown to attenuate cardiac myocyte hypertrophy, [5][6][7][8] to promote cardiac myocyte apoptosis, 9,10 and to modulate cardiac myocyte contractile function. 2,11 Studies in NOS2-deficient and NOS2-overexpressing mice indicate that upregulation of NOS2 is detrimental and may increase mortality in heart failure.…”

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confidence: 99%

Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide

et al. 2003

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Background-In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure. Methods and Results-As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeletonassociated muscle LIM protein (MLP) in endothelin-1 (ET-1)-stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (Ϫ49%, PϽ0.01) and protein (Ϫ52%, PϽ0.01) abundance in ET-1-treated cardiomyocytes via cGMPdependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1␤ and IFN-␥ downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (Ϫ52%, PϽ0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes. Conclusions-NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.

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“…4 Recent studies have shown that iNOS expression and activity are increased in the myocardium of failing hearts and result in increased NO levels in the circulation. [5][6][7][8][9] Although increased NO production from iNOS may decrease vascular resistance, which is beneficial, high levels of NO may also depress myocardial contractility and, through formation of peroxynitrite, may cause myocardial damage. 10 In the present study, we hypothesized that increased NO production from iNOS expression causes myocardial dysfunction and results in high mortality after myocardial infarction (MI).…”

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confidence: 99%

Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice

et al. 2001

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Background-Inducible nitric oxide synthase (iNOS) is expressed in the myocardium after myocardial infarction (MI) and in heart failure. Its pathophysiological role in these conditions, however, is not clear. We hypothesized that increased NO production from iNOS expression causes myocardial dysfunction and results in higher mortality after MI. Methods and Results-MI was induced by left coronary artery ligation in iNOSϪ/Ϫ mutant and wild-type mice. Mortality was followed up for 30 days. MI resulted in a significant increase in mortality in both iNOS Ϫ/Ϫ and wild-type mice compared with sham operation (PϽ0.01). Mortality was significantly decreased and LV myocardial contractility was increased, however, in iNOS Ϫ/Ϫ mice compared with the wild-type mice (PϽ0.05). Five days after MI, myocardial iNOS mRNA expression, plasma nitrate and nitrite concentrations, and myocardial and plasma nitrotyrosine levels were significantly increased in wild-type compared with iNOS Ϫ/Ϫ mutant mice (PϽ0.05). Both basal LV ϩdP/dt and its response to dobutamine were significantly increased in iNOS Ϫ/Ϫ compared with the wild-type mice (PϽ0.05). Conclusions-Increased NO production from iNOS expression contributes to myocardial dysfunction and mortality after MI in mice. (Circulation. 2001;104:700-704.)

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Inducible Nitric Oxide Synthase (iNOS) in the Human Heart: Expression and Localization in Congestive Heart Failure

Cited by 91 publications

References 3 publications

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide

Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice

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