Increased neuronal nitric oxide synthase-derived NO production in the failing human heart

Damy, Thibaud; Ratajczak, Philippe; Shah, Ajay M.; Camors, Emmanuel; Marty, Isabelle; Hasenfuß, Gerd; Marotte, F.; Samuel, Jane‐Lise; Heymes, Christophe

doi:10.1016/s0140-6736(04)16048-0

Cited by 231 publications

(189 citation statements)

References 7 publications

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“…It is established that both skeletal (32), and cardiac (31) RYRs are, in fact, activated by S-nitrosylation (33). The cardiac ryanodine isoform, which is S-nitrosylated under basal conditions, has been shown to colocalize with NOS1 in the SR (24,34). NOS1 positively modulates contractility, as demonstrated by depressed force frequency and ␤-adrenergic inotropic responses in NOS1-deficient mice (2,3).…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon can result from alterations in its regulatory pathways, [for example, ␤ 3 -AR signaling (39,40) or alterations in caveolin (28)]. Damy et al (34) demonstrated a disruption of the spatial localization of NOS1 (translocation from SR to sarcolemma) in tissue from patients with cardiomyopathy. Moreover, NOS1 was demonstrated to be up-regulated in these conditions.…”

Section: Discussionmentioning

confidence: 99%

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Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Steppan

Ryoo

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoformspecific regulation. One regulatory mechanism for NOS is substrate (L-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes L-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-L-cysteine (BEC) augmented Ca 2؉ -dependent NOS activity and NO production in myocytes, which did not depend on extracellular L-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxynor-L-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N G -nitro-L-arginine methyl ester and S-methyl-L-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted. mitochondria ͉ L-arginine pools ͉ spatial confinement

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Steppan

Ryoo

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The mechanism(s) for this effect remains controversial. One explanation derived from in vitro observations is that NOS3 inhibits the sarcolemmal L-type calcium channel on the sarcolemmal aspect of the dyad, whereas NOS1 modulates ryanodine receptor (RyR) activity on the sarcoplasmic reticulum (SR) (1)(2)(3). Although this paradigm explains many facets of NO activity within the heart, other studies suggest that in the myocyte, NOS1 may bind to and/or regulate other ion channels or effectors, including the plasma membrane calcium/calmodulin-dependent calcium ATPase (4), sarcoplamic reticulum Ca 2ϩ -ATPase (SERCA) (5), and possibly phospholamban (PLB).…”

mentioning

confidence: 99%

“…In heart failure and/or other states of cardiac injury, NOS1 levels within the heart rise, and NOS1 effectively translocates from the SR to the plasma membrane (2,7,8). Because this phenomenon could have either deleterious effects or adaptive consequences, it is imperative to address definitively the physiologic role of NOS1 in the heart.…”

mentioning

confidence: 99%

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

González

Beigi

Treuer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

201

192

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Altered Ca 2؉ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via Snitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca 2؉ homeostasis. Diastolic Ca 2؉ levels are elevated in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not NOS3 ؊/؊ myocytes compared with wild-type (WT), suggesting diastolic Ca 2؉ leakage. Measured leak was increased in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not in NOS3 ؊/؊ myocytes compared with WT. Importantly, NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1 ؊/؊ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca 2؉ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.heart ͉ nitric oxide ͉ excitation-contraction coupling ͉ oxidative stress ͉ heart failure T he cardiac myocyte has emerged as a prototypic example of the manner in which nitric oxide (NO) signaling occurs in a spatially confined manner. Although neuronal (NOS1) and endothelial (NOS3) isoforms of nitric oxide synthase are located extremely close to one another within the cell on opposite sides of the dyad, they exert opposite effects on myocardial contractility (1). The mechanism(s) for this effect remains controversial. One explanation derived from in vitro observations is that NOS3 inhibits the sarcolemmal L-type calcium channel on the sarcolemmal aspect of the dyad, whereas NOS1 modulates ryanodine receptor (RyR) activity on the sarcoplasmic reticulum (SR) (1-3). Although this paradigm explains many facets of NO activity within the heart, other studies suggest that in the myocyte, NOS1 may bind to and/or regulate other ion channels or effectors, including the plasma membrane calcium/calmodulin-dependent calcium ATPase (4), sarcoplamic reticulum Ca 2ϩ -ATPase (SERCA) (5), and possibly phospholamban (PLB). In addition, there is support for the notion that this effect is mediated by a direct protein posttranslational modification; but again, this assertion is controversial (6).Another facet of NO cardiobiology has emerged that further motivates the importance of understanding the direct NOS effector molecules. In heart failure and/or other states of cardiac injury, NOS1 levels within the heart rise, and NOS1 effectively translocates from the SR to the plasma membrane (2,7,8). Because this phenomenon could have either deleterious effects or adaptive consequences, it is imperative to address definitively the physiologic role of NOS1 in the heart.To address these issues, we tested the hypothesis that the cardiac RyR i...

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“…The importance of NOS-1 signaling in the heart is well established. NOS-1 ablation enhances basal contractility (33,34), and NOS-1-derived NO increases as a consequence of experimental and pathological human heart failure (35). It has recently been shown that NOS-1 expression is up-regulated in the final stages of late phase ischemic preconditioning (36), suggesting it may be important in protecting the heart against myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

The Sarcolemmal Calcium Pump, α-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex

Williams

Armesilla

Mohamed

et al. 2006

Journal of Biological Chemistry

134

118

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The main role of the plasma membrane Ca 2؉ /calmodulin-dependent ATPase (PMCA) is in the removal of Ca 2؉ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and ␣-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, ␣-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399 -447 of ␣-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of ␣-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of ␣-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4 ؊/؊ mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin⅐dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality.

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Increased neuronal nitric oxide synthase-derived NO production in the failing human heart

Cited by 231 publications

References 7 publications

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

The Sarcolemmal Calcium Pump, α-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex

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