NO and sGC-Stimulating NO Donors

Megson, Ian L.; Miller, Mark R.

doi:10.1007/978-3-540-68964-5_12

Cited by 10 publications

(8 citation statements)

References 61 publications

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“…[51] 2. [52] Stimulation of sGC inhibits TGF-β-induced fibroblast activation with decreased expression and release of collagen. These inhibitory effects, however, are not dependent on the typical TGF-β downstream mediator SMAD3, but on reductions of TGF-β-mediated ERK phosphorylation and activation.…”

Section: Fgfr2-iiib (Bemarituzumab) Fgfr3 (Mfgr1877s) and Fgf23mentioning

confidence: 99%

“…Upon binding of nitric oxide (NO), the soluble guanylate cyclase (sGC) catalyses the formation of cyclic guanosine monophosphate (cGMP) from guanosine‐5′‐triphosphate (GTP). Upon release from sGC, cGMP can act as a second messenger to activate further downstream targets, such as cGMP‐regulated ion channels, protein kinases (G‐kinases) and phosphodiesterases (PDEs), which regulate a variety of physiological processes, including cell growth and proliferation, vascular tone and remodelling, immune responses and neuronal transmission 52 …”

Section: Transforming Growth Factor β (Tgf‐β) Signalling—core Signallmentioning

confidence: 99%

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Cellular and molecular mechanisms in fibrosis

Dees

Chakraborty

Distler

2020

Experimental Dermatology

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Section: Fgfr2-iiib (Bemarituzumab) Fgfr3 (Mfgr1877s) and Fgf23mentioning

confidence: 99%

Section: Transforming Growth Factor β (Tgf‐β) Signalling—core Signallmentioning

confidence: 99%

Cellular and molecular mechanisms in fibrosis

Dees

Chakraborty

Distler

2020

Experimental Dermatology

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“…Clinical application of NO or NO-donating drugs, however, is hampered by insufficient biometabolism, rapid development of tolerance and non-specific interactions of NO with other biological molecules. In particular, prolonged application or high concentrations of NO induce oxidative stress, cause DNA damage, prompt lipid peroxidation and alter protein function, which includes oxidation of the sGC rendering the enzyme unresponsive to NO 10 11. Since oxidative stress has been implicated in fibroblast activation, the toxic effects of NO may be particularly harmful in patients with SSc 1.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling

et al. 2014

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ObjectivesWe have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor β (TGFβ) signalling that mediates the antifibrotic effects of the sGC.MethodsHuman fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGFβ. sGC knockout fibroblasts were isolated from sGCIfl/fl mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-β1 receptor.ResultssGC stimulation inhibited TGFβ-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGFβ-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFβ target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFβ-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFβ target gene expression, confirming that non-canonical TGFβ pathways mediate the antifibrotic sGC activity.ConclusionsWe elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFβ signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.

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“…Implication of Cav2-Enzyme Assemblies for Cell Physiology. Our results indicate that upon coassembly with Cav2.2 channels both NOS1 and PKCβ can be reliably activated by short action-potential-like membrane depolarization, an alternative to activation of PKC by exogenously administered DAG derivatives or the use of NO donors for delivery of NO (30,31). In addition, these results showed that operation and properties of the two Cav2-enzyme assemblies closely resembled those of Cav2-BK Ca complexes (32).…”

Section: Discussionmentioning

confidence: 53%

Identification of Cav2–PKCβ and Cav2–NOS1 complexes as entities for ultrafast electrochemical coupling

Constantin¹,

Müller²,

Leitner³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-activated calcium (Cav) channels couple intracellular signaling pathways to membrane potential by providing Ca ions as second messengers at sufficiently high concentrations to modulate effector proteins located in the intimate vicinity of those channels. Here we show that protein kinase Cβ (PKCβ) and brain nitric oxide synthase (NOS1), both identified by proteomic analysis as constituents of the protein nano-environment of Cav2 channels in the brain, directly coassemble with Cav2.2 channels upon heterologous coexpression. Within Cav2.2-PKCβ and Cav2.2-NOS1 complexes voltage-triggered Ca influx through the Cav channels reliably initiates enzymatic activity within milliseconds. Using BK channels as target sensors for nitric oxide and protein phosphorylation together with high concentrations of Ca buffers showed that the complex-mediated Ca signaling occurs in local signaling domains at the plasma membrane. Our results establish Cav2-enzyme complexes as molecular entities for fast electrochemical coupling that reliably convert brief membrane depolarization into precisely timed intracellular signaling events in the mammalian brain.

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NO and sGC-Stimulating NO Donors

Cited by 10 publications

References 61 publications

Cellular and molecular mechanisms in fibrosis

Cellular and molecular mechanisms in fibrosis

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling

Identification of Cav2–PKCβ and Cav2–NOS1 complexes as entities for ultrafast electrochemical coupling

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