H2O2 lowers the cytosolic Ca2+ concentration via activation of cGMP-dependent protein kinase Iα

Müller, Paul Markus; Gnügge, Robert; Dhayade, Sandeep; Thunemann, Martin; Koehler, Peter; Drews, Gisela; Feil, Robert

doi:10.1016/j.freeradbiomed.2012.08.011

Cited by 26 publications

(28 citation statements)

References 54 publications

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“…disulfide desensitizes the kinase to cGMP-dependent phosphorylation of VASP (vasodilator-stimulated phosphoprotein) protein (9). Because cGMP abrogates disulfide formation in PKG I␣ (8, 9), we conclude that each mode of activation reciprocally negatively regulates the alternate mechanism as illustrated in Fig.…”

Section: Discussionmentioning

confidence: 74%

“…Because tadalafil increases cGMP, we reasoned that the protective effect of this long half-life PDE5 inhibitor involved it blocking PKG oxidation to the activated disulfide state. This was plausible because two independent previous studies showed that cGMP blocks PKG oxidation (8,9). Indeed, this turned out to be the case, with tadalafil limiting increases in disulfide PKG I␣ occurring during either acute (several hours) or chronic (5 days) exposure to doxorubicin.…”

Section: Discussionmentioning

confidence: 93%

“…When cGMP binds PKG I␣, it attenuates oxidant-induced disulfide formation (8,9). Because inhibition of PDE5 elevates cGMP and also provides protection from doxorubicin-or pressure overload-induced injury, we reasoned that this may be because it limits oxidation of the kinase to the disulfide.…”

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confidence: 99%

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Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Prysyazhna¹,

Burgoyne²,

Scotcher³

et al. 2016

Journal of Biological Chemistry

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Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG I␣ attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG I␣ disulfide formation. To investigate the role of PKG I␣ disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG I␣ knock-in (KI) mice. Echocardiography showed that doxorubicin treatment caused loss of myocardial tissue and depressed left ventricular function in WT mice. Doxorubicin also reduced pro-survival signaling and increased apoptosis in WT hearts. In contrast, KI mice were markedly resistant to the dysfunction induced by doxorubicin in WTs. In follow-on experiments the influence of the PDE5 inhibitor tadalafil on the development of doxorubicin-induced cardiomyopathy in WT and KI mice was investigated. In WT mice, co-administration of tadalafil with doxorubicin reduced PKG I␣ oxidation caused by doxorubicin and also protected against cardiac injury and loss of function. KI mice were again innately resistant to doxorubicin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associated protein kinase (ROCK) in WTs. These pro-apoptotic events were absent in KI mice and were attenuated in WTs coadministered tadalafil. PKG I␣ disulfide formation triggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 93%

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Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Prysyazhna¹,

Burgoyne²,

Scotcher³

et al. 2016

Journal of Biological Chemistry

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“…A novel mechanism of relaxation to peroxide by a cGMP-independent thiol oxidation-elicited dimerization-activation of the 1␣ form of protein kinase G (PKG1␣) was first reported in the aorta and coronary circulation of rats (2). In addition, recent studies, including the use of mice lacking PKG1␣ or possessing a knockin form of PKG1␣ that cannot dimerize, provide evidence that this form of PKG is a key mediator of relaxation to peroxide in systemic arteries, with properties of it functioning as an endothelium-derived hyperpolarizing factor (16,21,25). We found that the peroxideelicited PKG dimerization mechanism was also present in BPA (18) and that it participated in responses to hypoxia in both BPA and coronary arteries (20).…”

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confidence: 99%

Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1α

Neo

Patel

Kandhi

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Neo BH, Patel D, Kandhi S, Wolin MS. Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1␣. Am J Physiol Heart Circ Physiol 305: H330 -H343, 2013. First published May 24, 2013 doi:10.1152/ajpheart.01010.2011.-The activity of glucose-6-phosphate dehydrogenase (G6PD) appears to control a vascular smooth muscle relaxing mechanism regulated through cytosolic NADPH oxidation. Since our recent studies suggest that thiol oxidation-elicited dimerization of the 1␣ form of protein kinase G (PKG1␣) contributes to the relaxation of isolated endothelium-removed bovine pulmonary arteries (BPA) to peroxide and responses to hypoxia, we investigated whether cytosolic NADPH oxidation promoted relaxation by PKG1␣ dimerization. Relaxation of BPA to G6PD inhibitors 6-aminonicotinamide (6-AN) and epiandrosterone (studied under hypoxia to minimize basal levels of NADPH oxidation and PKG1␣ dimerization) was associated with increased PKG1␣ dimerization and PKG-mediated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Depletion of PKG1␣ by small inhibitory RNA (siRNA) inhibited relaxation of BPA to 6-AN and attenuated the increase in VASP phosphorylation. Relaxation to 6-AN did not appear to be altered by depletion of soluble guanylate cyclase (sGC). Depletion of G6PD, thioredoxin-1 (Trx-1), and Trx reductase-1 (TrxR-1) in BPA with siRNA increased PKG1␣ dimerization and VASP phosphorylation and inhibited force generation under aerobic and hypoxic conditions. Depletion of TrxR-1 with siRNA inhibited the effects of 6-AN and enhanced similar responses to peroxide. Peroxiredoxin-1 depletion by siRNA inhibited PKG dimerization to peroxide, but it did not alter PKG dimerization under hypoxia or the stimulation of dimerization by 6-AN. Thus regulation of cytosolic NADPH redox by G6PD appears to control PKG1␣ dimerization in BPA through its influence on Trx-1 redox regulation by the NADPH dependence of TrxR-1. NADPH regulation of PKG dimerization may contribute to vascular responses to hypoxia that are associated with changes in NADPH redox.glucose-6-phosphate dehydrogenase; hypoxia; thioredoxin OUR LABORATORY has previously reported evidence for the existence of a relaxing mechanism coordinated by the oxidation of cytosolic NADPH generated by the pentose phosphate pathway (9) that appeared to participate in the responses of bovine coronary arteries and bovine pulmonary arteries (BPA) to hypoxia (10 -12). Initial studies investigating the mechanism of relaxation to 6-aminonicotinamide (6-AN) and epiandrosterone (Epi), inhibitors of glucose-6-phosphate dehydrogenase (G6PD), in bovine coronary arteries and BPA detected evidence that cytosolic NADPH oxidation appeared to coordinate multiple processes decreasing the levels and actions of intracellular calcium (9,11,12). The inhibition of G6PD by these agents also appeared to lower the detection of reactive oxygen species (ROS) derived from Nox oxidases by decreasing the levels of cytosolic NADPH ...

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“…Interestingly, cGKI also mediates cGMP–Ca 2+ crosstalk in vascular smooth muscle cells. However, activation of cGKI in these cells typically results in suppression of agonist-evoked increases of [Ca 2+ ] i [42,43,44], suggesting that cGKI is not the effector of the NO-cGMP-mediated increase of [Ca 2+ ] i observed in CGNs. Indeed, Western blot analysis did not detect cGKI or cGKII protein expression in our primary mouse CGNs.…”

Section: Discussionmentioning

confidence: 99%

Real-Time Imaging Reveals Augmentation of Glutamate-Induced Ca2+ Transients by the NO-cGMP Pathway in Cerebellar Granule Neurons

Paolillo

Peters

Schramm

et al. 2018

IJMS

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Dysfunctions of NO-cGMP signaling have been implicated in various neurological disorders. We have studied the potential crosstalk of cGMP and Ca2+ signaling in cerebellar granule neurons (CGNs) by simultaneous real-time imaging of these second messengers in living cells. The NO donor DEA/NO evoked cGMP signals in the granule cell layer of acute cerebellar slices from transgenic mice expressing a cGMP sensor protein. cGMP and Ca2+ dynamics were visualized in individual CGNs in primary cultures prepared from 7-day-old cGMP sensor mice. DEA/NO increased the intracellular cGMP concentration and augmented glutamate-induced Ca2+ transients. These effects of DEA/NO were absent in CGNs isolated from knockout mice lacking NO-sensitive guanylyl cyclase. Furthermore, application of the cGMP analogues 8-Br-cGMP and 8-pCPT-cGMP, which activate cGMP effector proteins such as cyclic nucleotide-gated cation channels and cGMP-dependent protein kinases (cGKs), also potentiated glutamate-induced Ca2+ transients. Western blot analysis failed to detect cGK type I or II in our primary CGNs. The addition of phosphodiesterase (PDE) inhibitors during cGMP imaging showed that CGNs degrade cGMP mainly via Zaprinast-sensitive PDEs, most likely PDE5 and/or PDE10, but not via PDE1, 2, or 3. In sum, these data delineate a cGK-independent NO-cGMP signaling cascade that increases glutamate-induced Ca2+ signaling in CGNs. This cGMP–Ca2+ crosstalk likely affects neurotransmitter-stimulated functions of CGNs.

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H2O2 lowers the cytosolic Ca2+ concentration via activation of cGMP-dependent protein kinase Iα

Cited by 26 publications

References 54 publications

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1α

Real-Time Imaging Reveals Augmentation of Glutamate-Induced Ca2+ Transients by the NO-cGMP Pathway in Cerebellar Granule Neurons

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