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Prevention of PKG-1? Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.

ABSTRACT: BACKGROUND:Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1? to counteract cardiac hypertrophy and failure. PKG1? acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1? oxidation might also differentially influence the effects from their pharmacological modulation. METHODS AND RESULTS:Knock-in mice expressing a redox-dead PKG1? (PKG1?C42S) or littermate controls (PKG1?WT) were subjected to transaortic constriction to induce pressure overload and treated with a PDE5 inhibitor (sildenafil), sGC activator (BAY602770 [BAY]), or vehicle. In PKG1?WT controls, sildenafil and BAY similarly enhanced PKG activity and reduced pathological hypertrophy/fibrosis and cardiac dysfunction after transaortic constriction. However, sildenafil failed to protect the heart in PKG1?C42S, unlike BAY, which activated PKG and thereby facilitated protective effects. This corresponded with minimal PDE5 activation in PKG1?C42S exposed to transaortic constriction versus higher activity in controls and little colocalization of PDE5 with PKG1?C42S (versus colocalization with PKG1?WT) in stressed myocytes. CONCLUSIONS:In the stressed heart and myocytes, PKG1? C42-disulfide formation contributes to PDE5 activation. This augments the pathological role of PDE5 and so in turn enhances the therapeutic impact from its inhibition. PKG1? oxidation does not change the benefits from sGC activation. This finding favors the use of sGC activators regardless of PKG1? oxidation and may help guide precision therapy leveraging the cyclic GMP/PKG pathway to treat heart disease.

SUBMITTER: Nakamura T

PROVIDER: S-EPMC5858464 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.

Nakamura Taishi T Zhu Guangshuo G Ranek Mark J MJ Kokkonen-Simon Kristen K Zhang Manling M Kim Grace E GE Tsujita Kenichi K Kass David A DA

Circulation. Heart failure 20180301 3

<h4>Background</h4>Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1α to counteract cardiac hypertrophy and failure. PKG1α acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1α oxidation might also differenti ...[more]

PMID: 29545395

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Project description:Background:Ischemic stroke remains the leading cause of death and adult disability. Cerebral ischemic/reperfusion (I/R) injury is caused by ischemic stroke thereafter aggravates overwhelming neuronal apoptosis and even the death of neurons. Of note, hippocampus is more susceptive to cerebral I/R injury than the other brain region. This study was designed to explore the effects and mechanism of icariside II (ICS II), a pharmacologically active compound exists in herbal Epimedii with previous study-proved as a phosphodiesterase 5 (PDE5) inhibitor, on the oxygen glucose deprivation/reoxygenation (OGD/R)-induced primary hippocampal neurons injury. Methods:Effects of ICS II on primary hippocampal neuronal impairment and apoptosis induced by OGD/R were examined by MTT, lactate dehydrogenase (LDH) release, TUNEL staining, and flow cytometry, respectively. Activation of memory-related signaling pathways was measured using Western blot analysis. The direct interaction between ICS II and PDE5 was further evaluated by molecular docking. Results:ICS II (12.5, 25, 50 ?M) markedly abrogated OGD/R-induced hippocampal neuronal death as suggested by the increase in neurons viability and the decrease in cellular LDH release. Furthermore, ICS II not only effectively decreased the protein expression and activity of PDE5, restored the 3'5'-cyclic guanosine monophosphate (cGMP) level and its downstream target protein kinase G (PKG) activity but also increased the phosphorylation of cAMP response element binding protein (CREB) level, expressions of brain derived neurotrophic factor (BDNF), and tyrosine protein kinase B (TrkB). Mechanistically, the inhibitory effects of ICS II were abrogated by Rp-8-Br-cGMP (a PKG inhibitor) or ANA-12 (a TrkB inhibitor), which further confirmed that the favorable effects of ICS II were attributed to its activation of the PKG/CREB/BDNF signaling pathways. Intriguingly, ICS II might effectively bind and inhibited PDE5 activity as demonstrated by relatively high binding scores (-6.52 kcal/mol). Conclusions:ICS II significantly rescues OGD/R-induced hippocampal neuronal injury. The mechanism is, at least partly, due to inhibition of PDE5 and activation of PKG/CREB/BDNF/TrkB signaling pathway. Hence it is thought that ICS II might be a potential naturally PDE5 inhibitor to combat cerebral I/R injury.

Project description:BACKGROUND:Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis and activates several signaling pathways. However, the mechanisms underlying OMS remain unclear. Here, we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS. METHODS:The activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines, and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia-conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated. RESULTS:Incubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells. Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB. Furthermore, the expression of NO, sGC, and PKG was increased. Neuronal cytolysis was relieved by the inhibitors of NO signaling, while neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. The cytolysis of neurons was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG. CONCLUSIONS:Serum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate.

Dataset Information

Prevention of PKG-1? Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.

Publications

Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.

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