Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

Burkard, Natalie; Rokita, Adam G.; Kaufmann, Susann G.; Hallhuber, Matthias; Wu, Rongxue; Hu, Kai; Hofmann, Ulrich; Bonz, Andreas; Frantz, Stefan; Cartwright, Elizabeth J.; Neyses, Ludwig; Maier, Lars S.; Maier, Sebastian; Renné, Thomas; Schuh, Kai; Ritter, Oliver

doi:10.1161/01.res.0000259042.04576.6a

Cited by 89 publications

(79 citation statements)

References 40 publications

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“…Interestingly, although CAPON overexpression activates NOS1-derived NO in our work, the electrophysiological changes mediated by this NO activation are comparable with those in previous reports (17)(18)(19)21). Recently, evidence emerged that NOS1 may play a critical role in the regulation of calcium handling and myocyte contraction in the heart (9,10,12,22). Burkard et al (12) observed that in a conditional NOS1-overexpressing transgenic mouse model, the peak I Ca,L density was significantly reduced by 39% in NOS1-overexpressing ventricular myocytes, which was attributed to the translocation of NOS1 to sarcolemma where NOS1 interacted with L-type calcium channel and caused inhibition of I Ca,L .…”

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalsupporting

confidence: 91%

“…This investigation might be of particular importance, because NOS1-NO pathways have recently been related to play a role in regulating cardiac contractility (9,10,12). Moreover, because CAPON may compete with other PDZ-binding proteins for PDZ binding, it is likely that CAPON, in addition to modulating the NOS1-NO pathway, might also have other biological effects, particularly regarding stabilization of cell membrane proteins, including ion channels.…”

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalmentioning

confidence: 99%

“…In the sarcoplasmic reticulum (SR), NOS1 is structurally associated with ryanodine receptor 2 (RyR2) (10) and cardiac SR Ca 2ϩ ATPase (SERCA2) (11) to regulate intracellular calcium cycling and excitation-contraction coupling. Conditional transgenic overexpression of NOS1 in heart leads to additional association of NOS1 and the sarcolemmal L-type calcium channel and thus suppresses the L-type calcium currents (I Ca,L ) (12). All of these lines of evidence highlight the notion that NOS1 plays a key role in regulating cardiac physiology.…”

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confidence: 94%

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CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

Chang

Barth

Sasano

et al. 2008

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

142

112

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Congenital long-or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from the rare disease-causing mutations, common genetic variants in CAPON, a neuronal nitric oxide synthase (NOS1) regulator, have recently been associated with QT interval variations in a human whole-genome association study. CAPON had been unsuspected of playing a role in cardiac repolarization; indeed, its physiological role in the heart (if any) is unknown. To define the biological effects of CAPON in the heart, we investigated endogenous CAPON protein expression and protein-protein interactions in the heart and performed electrophysiological studies in isolated ventricular myocytes with and without CAPON overexpression. We find that CAPON protein is expressed in the heart and interacts with NOS1 to accelerate cardiac repolarization by inhibition of L-type calcium channel. Our findings provide a rationale for the association of CAPON gene variants with extremes of the QT interval in human populations.NOS1 ͉ QT interval ͉ cardiac electrophysiology R are disease-causing mutations leading to congenital long-or short-QT syndrome are well recognized, but there is little insight into genetic sources of QT interval variation in normal populations. A whole-genome association approach has recently implicated common genetic variants in CAPON as contributing to QT interval differences in a community-based German population (1). This association has since been confirmed in other populations (2, 3). The genetic findings challenge our current understanding of QT physiology. CAPON, first identified in rat brain neurons (4), is a highly conserved protein (Ϸ92% conceptual amino acid sequence identity between rat and human) with an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal PDZ-binding [postsynaptic density-95 (PSD95)/drosophila discs large/zona occludens-1] domain (4-6). In brain, CAPON competes with PSD95 for the binding of neuronal nitric oxide synthase (NOS1) through the interaction of its C terminus with the PDZ domain of NOS1 (4), thus uncoupling the NMDA-NOS1-NO-mediated signaling pathways. CAPON is also an adaptor protein of NOS1, capable of directing NOS1 to specific target proteins (5, 6). Nowhere, however, has CAPON been suspected of playing a role in cardiac physiology.Both NOS1 and endothelial NOS (NOS3) are constitutively expressed in cardiomyocytes (7). NOS1 in the sarcolemma has been proposed to interact with Na ϩ -K ϩ ATPase (8) and with the plasma membrane Ca 2ϩ /calmodulin-dependent Ca 2ϩ ATPase (PMCA) through the interaction of PDZ domain of NOS1 and the C terminus of PMCA4b isoform (9). In the sarcoplasmic reticulum (SR), NOS1 is structurally associated with ryanodine receptor 2 (RyR2) (10) and cardiac SR Ca 2ϩ ATPase (SERCA2) (11) to regulate intracellular calcium cycling and excitation-contraction coupling. Conditional transgenic overexpression of NOS1 in heart leads to additional association of NOS1 and the sarcolemmal L-type calcium channel and thus suppresses...

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Section: Reversal Of Capon Overexpression-induced Electrophysiologicalsupporting

confidence: 91%

Section: Reversal Of Capon Overexpression-induced Electrophysiologicalmentioning

confidence: 99%

mentioning

confidence: 94%

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CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

Chang

Barth

Sasano

et al. 2008

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

142

112

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“…In separate lines of work, several groups, including our own, have demonstrated the presence of NOS1 in the cardiac SR in proximity to RyR2 (5,23,24). Recently, it has been shown that increasing the frequency of stimulation activates NO production from NOS1, in a calmodulin-dependent manner (25).…”

Section: Discussionmentioning

confidence: 92%

“…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). 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).…”

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.

199

191

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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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Inducible over‐expression of cardiac Nos1ap causes short QT syndrome in transgenic mice

et al. 2022

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Recent evidence demonstrated that alterations in the QT interval duration on the ECG are not only determined by mutations in genes for ion channels, but also by modulators of ion channels. Changes in the QT interval duration beyond certain thresholds are pathological and can lead to sudden cardiac death. We here focus on the ion channel modulator nitric oxide synthase 1 adaptor protein (Nos1ap). Whole‐cell patch‐clamp measurements of a conditional transgenic mouse model exhibiting cardiac‐specific Nos1ap over‐expression revealed a Nos1ap‐dependent increase of L‐type calcium channel nitrosylation, which led to increased susceptibility to ventricular tachycardias associated with a decrease in QT duration and shortening of APD 90 duration. Survival was significantly reduced (60% after 12 weeks vs. 100% in controls). Examination of the structural features of the hearts of transgenic mice revealed constant heart dimensions and wall thickness without abnormal fibrosis content or BNP production after 3 months of Nos1ap over‐expression compared to controls. Nos1ap over‐expression did not alter cGMP production or ROS concentration. Our study showed that myocardial over‐expression of Nos1ap leads to the shortening of the QT interval and reduces the survival rate of transgenic animals, perhaps via the development of ventricular arrhythmias. We conclude that Nos1ap overexpression causes targeted subcellular localization of Nos1 to the CaV1.2 with a subsequent decrease of ADP 90 and the QT interval. This causes detrimental cardiac arrhythmias in transgenic mice.

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Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

Cited by 89 publications

References 40 publications

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

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

Inducible over‐expression of cardiac Nos1ap causes short QT syndrome in transgenic mice

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