Nitric oxide-mediated alterations of protein tyrosine phosphatase activity and expression during hypoxia in the cerebral cortex of newborn piglets

Ashraf, Qazi M.; S, Haider; Katsetos, Christos D.; Delivoria‐Papadopoulos, Maria; Mishra, O. M. P.

doi:10.1016/j.neulet.2004.02.069

Cited by 20 publications

(8 citation statements)

References 21 publications

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“…For instance, inhibition of nNOS in the cerebral cortex has been shown to prevent the hypoxiainduced decrease in phosphatase activity at the cellular membrane while suppressing the increase in phosphatase activity in the cytosol through a cGMP-independent mechanism. 32 Although these examples are not directly pertinent to the regulation of PLN phosphorylation in the myocardium, they show that modulation of phosphatase activity by ROS or nNOS-derived NO is possible and may vary in different subcellular compartments. Taken together with recent data indicating that oxidant stress can directly activate PKA and cause the kinase to relocalize to specific subcellular domains, 20 these findings indicate that protein phosphorylation can be regulated by the NO/redox state of the myocardium, both through the well-established cGMP-dependent effects on PDE activity 19 and through a cGMP-independent regulation of PKA and PP activity leading to subcellular targeting and compartmentalization of cAMP-mediated signaling.…”

Section: Regulation Of Pln Phosphorylation By Nnos-derived Nomentioning

confidence: 99%

Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase–Deficient Mice

Zhang

Sears

et al. 2008

Circulation Research

110

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Abstract-Stimulation of nitric oxide (NO) release from the coronary endothelium facilitates myocardial relaxation via a cGMP-dependent reduction in myofilament Ca 2ϩ sensitivity. Recent evidence suggests that NO released by a neuronal NO synthase (nNOS) in the myocardium can also hasten left ventricular relaxation; however, the mechanism underlying these findings is uncertain. Here we show that both relaxation (TR 50 ) and the rate of [Ca 2ϩ ] i transient decay (tau) are significantly prolonged in field-stimulated or voltage-clamped left ventricular myocytes from nNOS Ϫ/Ϫ mice and in wild-type myocytes (nNOS ϩ/ϩ ) after acute nNOS inhibition. Disabling the sarcoplasmic reticulum abolished the differences in TR 50 and tau, suggesting that impaired sarcoplasmic reticulum Ca 2ϩ reuptake may account for the slower relaxation in nNOS Ϫ/Ϫ mice. In line with these findings, disruption of nNOS (but not of endothelial NOS) decreased phospholamban phosphorylation (P-Ser 16 PLN), whereas nNOS inhibition had no effect on TR 50 or tau in PLN Ϫ/Ϫ myocytes. Inhibition of cGMP signaling had no effect on relaxation in either group whereas protein kinase A inhibition abolished the difference in relaxation and PLN phosphorylation by decreasing P-Ser 16 PLN and prolonging TR 50 in nNOS ϩ/ϩ myocytes. Conversely, inhibition of type 1 or 2A protein phosphatases shortened TR 50 and increased P-Ser 16 PLN in nNOS Ϫ/Ϫ but not in nNOS ϩ/ϩ myocytes, in agreement with data showing increased protein phosphatase activity in nNOS Ϫ/Ϫ hearts. Taken together, our findings identify a novel mechanism by which myocardial nNOS promotes left ventricular relaxation by regulating the protein kinase A-mediated phosphorylation of PLN and the rate of sarcoplasmic reticulum Ca 2ϩ reuptake via a cGMP-independent effect on protein phosphatase activity. Key Words: neuronal NOS Ⅲ nitric oxide Ⅲ relaxation Ⅲ phospholamban Ⅲ phosphatases T he facilitatory effects of nitric oxide (NO) on myocardial relaxation and left ventricular (LV) diastolic distensibility are well documented. In animal models and in humans, stimulation of NO release from the coronary endothelium hastens relaxation and enhances LV compliance. 1 The paracrine effects of endothelial-derived NO can be reproduced by applying cGMP analogs to isolated LV myocytes 2 and have been attributed to a reduction in myofilament Ca 2ϩ sensitivity secondary to troponin I phosphorylation by the cGMPdependent protein kinase (PK)G. 3 Through this mechanism, endogenous NO production may facilitate the Frank-Starling response 4 and maintain the LV preload reserve in failing hearts. 5 In contrast, the involvement of myocardial NO production in the regulation of relaxation has remained a matter of debate.An autocrine effect of NO on myocardial relaxation was first suggested in 1999, when inhibition of a neuronal-like NOS (nNOS) localized to the sarcoplasmic reticulum (SR) of LV myocytes was shown to increase the thapsigarginsensitive Ca 2ϩ uptake from cardiac SR vesicles. 6 These data implied that constitutiv...

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Section: Regulation Of Pln Phosphorylation By Nnos-derived Nomentioning

confidence: 99%

Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase–Deficient Mice

Zhang

Sears

et al. 2008

Circulation Research

110

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“…Firstly, it is now well recognized that PTP-1B can regulate the phosphorylation status of apoptotic proteins, which determines the anti-as well as pro-apoptotic potential of these proteins [25]. In addition, PTP-1B is transcriptionally upregulated in the cytosol of the piglet cerebral cortex cells when exposed to hypoxia [26] and levels of PTP-1B determine susceptibility to apoptosis in serum-deprived hepatocytes [23]. In particular, a recent report indicated that elevated PTP-1B expression was also observed in cardiomyocytes when cardiac function declined with advanced age [27].…”

Section: Introductionmentioning

confidence: 99%

Small interference RNA against PTP-1B reduces hypoxia/reoxygenation induced apoptosis of rat cardiomyocytes

2008

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“…There are different and competing cellular mechanisms that regulate PTP-1B activation. PTP-1B activation in brain samples, posthypoxia, increases in the cytosolic fraction of the cortical cells but decreases in the fraction derived from cellular membranes [17]. This possibly represents a localization effect of the PTP-1B as well as a difference in the status of enzymatic activation.…”

Section: Discussionmentioning

confidence: 99%

“…Src kinase activation was increased by LPS and Src activity was significantly inhibited by PTP-1B pretreatment. We have previously shown that pretreatment with a selective NOS inhibitor decreases the hypoxia-induced modification in the activity and expression of PTP [17] while in the study of Song et al, NO production was increased in cells overexpressing PTP-1B and treatment with PP2 significantly decreased its production [21]. …”

Section: Discussionmentioning

confidence: 99%

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

Angelis

Delivoria‐Papadopoulos

2017

Mediators of Inflammation

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Background Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. Methods Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. Results PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. Conclusions Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

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Nitric oxide-mediated alterations of protein tyrosine phosphatase activity and expression during hypoxia in the cerebral cortex of newborn piglets

Cited by 20 publications

References 21 publications

Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase–Deficient Mice

Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase–Deficient Mice

Small interference RNA against PTP-1B reduces hypoxia/reoxygenation induced apoptosis of rat cardiomyocytes

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

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