Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

Khan, Shakil A.; Lee, Kwang-Ho; Minhas, Khalid M.; González, Daniel; Raju, Sarath; Tejani, Ankit D.; Li, Dechun; Berkowitz, Dan E.; Hare, Joshua M.

doi:10.1073/pnas.0404136101

Cited by 215 publications

(226 citation statements)

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“…The biphasic nature of SIN-1 may relate to the physiological regulation of basal and submaximal β-adrenergic-stimulated contractility with low peroxynitrite production (i.e., NOS1) [40], and the pathophysiological regulation of chronic β-adrenergic stimulation with high peroxynitrite production (i.e., NOS2), as occurs in heart failure [3]. Thus, it appears that low SIN-1 may potentially mimic the peroxynitrite production of NOS1, which is hypothesized to produce low concentrations of peroxynitrite due to a co-localization with xanthine oxidase [4]. NOS1 is considered a physiological regulator of cardiac function and is also thought to increase myocardial contractility [41].…”

Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

“…Neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3) are constitutively expressed, while inducible NOS (iNOS, NOS2) is only expressed during immune responses and many pathophysiological conditions of the myocardium, such as heart failure [3]. NOS1 co-localizes with xanthine oxidase [4], a superoxide (O 2 .-) producing enzyme, and may potentially lead to the production of low levels of peroxynitrite (ONOO − ), as nitric oxide and superoxide react with a very high rate constant [5]. When expressed, NOS2 is capable of producing large amounts of both nitric oxide and superoxide [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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“…Specifically, in the sarcoplasmic reticulum (SR), NOS1 colocalizes with the ryanodine receptor (RYR), and activation of NOS1 positively modulates cardiac contractility. Also, NOS1 deficiency leads to an increase in xanthine oxidasedependent reactive-oxygen species activity, which dramatically depresses myocardial contractile function (4). In contrast, the NOS3 isoform coupled to the ␤ 3 adrenergic receptor (AR), inhibits L-type Ca 2ϩ channels and, thus, inhibits ␤-AR-mediated increases in myocardial contractility (5).…”

mentioning

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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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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“…More recently, NO has been recognized for its role in normal physiology, arising in part from its ability to act as a signal through regulation of guanylate cyclase (3) and to S-nitrosylate cysteinyl residues of proteins and peptides (3). In a recent issue of PNAS, we witnessed the emergence of a new paradigm wherein the interplay between different highly reactive species allows for complex and fast regulation of cellular processes whose disruption has potentially serious pathological consequences (4).…”

mentioning

confidence: 99%

“…Within the myocyte there are three direct reaction pathways for NO: reaction with a target protein, namely, RyR (8); consumption via reaction with superox-ide produced by XOR (4); and reaction with myoglobin in a way that NO cannot traverse the cytosolic space (14). What Khan et al (4) have made evident is that NOS activity is very tightly regulated temporally, spatially, and quantitatively. Another key aspect of their study is that NO may serve not only to regulate particular protein targets but also to control another reactive diffusible signaling species.…”

mentioning

confidence: 99%