Regulation of Endothelial Nitric-oxide Synthase (NOS) S-Glutathionylation by Neuronal NOS

Idigo, W; Reilly, Svetlana; Zhang, Mei Hua; Zhang, Yin Hua; Jayaram, Raja; Carnicer, Ricardo; Crabtree, Mark J.; Balligand, Jean‐Luc; Casadei, Barbara

doi:10.1074/jbc.m112.412031

Cited by 44 publications

(23 citation statements)

References 46 publications

(89 reference statements)

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“…1B–D). Conversely, the eNOS inhibitor L-NAME at dose of 20 mg/kg did not reverse the amelioration conferred by Bay 60-7550 although a higher dose of L-NAME inhibits both eNOS and nNOS based on the previous study (Idigo et al, 2012). Similarly, PKA inhibitor H89 (5 µM, 30 min) did not completely reverse the effect of Bay 60-7550.…”

Section: Resultsmentioning

confidence: 78%

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

Xu¹,

Pan²,

Sun³

et al. 2015

Neurobiology of Aging

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Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphological and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze (MWM), novel object recognition and location tasks (ORT/OLT), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase (nNOS); MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a PKG inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP or KT5823. PDE2 inhibition reduced stress-induced ERK activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and pCREB) and plasticity-related proteins (e.g, Egr-1 and BDNF). Pre-treatment with inhibitors of NMDA, CaMKII, nNOS, PKG (or PKA), blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related, NMDAR-CaMKII-cGMP/cAMP signaling.

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Section: Resultsmentioning

confidence: 78%

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

Xu¹,

Pan²,

Sun³

et al. 2015

Neurobiology of Aging

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“…This was suggested by our studies in the S1412A mutants that inhibited the BRL-induced augmentation of NOS activity, yet still exhibited an antioxidant effect from β3-AR stimulation. Other studies have also suggested that myocardial nNOS can interact specifically with xanthine oxidase reductase (XOR) derived

{normalO}_{2}^{-}

[15,29,30], thought to be primarily due to co-localization at the sarcoplasmic reticular membrane. More recently, Idigo et al showed that XOR inhibition restores β3 negative inotropy as well as eNOS coupling in nNOS −/− myocytes [15].…”

Section: Discussionmentioning

confidence: 99%

“…The negative inotropic effect of β3-AR stimulation involves NOS/NO signaling [2,5,10,11], and while it was initially thought to be due to endothelial NOS (eNOS), new data has shown that neuronal NOS (nNOS) also plays a key role [12–15]. In mice with nNOS genetically deleted or acutely inhibited, β3-AR-dependent cardiac protection, NO generation, and NOS downstream signaling are lacking in failing mouse myocardium [10,11].…”

Section: Introductionmentioning

confidence: 99%

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation

Watts

Sepulveda

Cingolani

et al. 2013

Journal of Molecular and Cellular Cardiology

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Rationale Stimulation of β3-adrenoreceptors (β3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and β3-AR protective signaling has yet to be explored. Objective We tested the hypothesis that β3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. Methods and results Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased β3-AR gene expression. Co-administration of the β3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. Conclusion β3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to β3-AR receptor stimulation.

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“…Similarly, the loss or oxidation of BH 4 enhances the glutathionylation of eNOS [42]. Interestingly, nNOS has been shown to regulate the activity of xanthine oxidoreductase, such that the loss of nNOS results in an increase in superoxide, which subsequently leads to an increase in the S-glutathionylation and uncoupling of eNOS [68]. The lack of benefit with BH 4 administration may be due to the continued cycle of NOS uncoupling (due to glutathionylation) and ROS generation, leading to the oxidation of BH 4 .…”

Section: Redox Regulation Of No Signaling and Dysregulation In Carmentioning

confidence: 99%

Signaling by S-nitrosylation in the heart

Murphy

Kohr

Menazza

et al. 2014

Journal of Molecular and Cellular Cardiology

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Nitric oxide is a gaseous signaling molecule that is well-known for the Nobel prize-winning research that defined nitric oxide as a physiological regulator of blood pressure in the cardiovascular system. Nitric oxide can signal via the classical pathway involving activation of guanylyl cyclase or by a post-translational modification, referred to as S-nitrosylation (SNO) that can occur on cysteine residues of proteins. As proteins with cysteine residues are common, this allows for amplification of the nitric oxide signaling. This review will focus on the possible mechanisms through which SNO can alter protein function in cardiac cells, and the role of SNO occupancy in these mechanisms. The specific mechanisms that regulate protein SNO, including redox-dependent processes, will also be discussed.

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Regulation of Endothelial Nitric-oxide Synthase (NOS) S-Glutathionylation by Neuronal NOS

Cited by 44 publications

References 46 publications

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation

Signaling by S-nitrosylation in the heart

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