Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Tawa, Masashi; Okamura, Tomio

doi:10.1002/prp2.261

Cited by 18 publications

(11 citation statements)

References 44 publications

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“…In sGC stimulator, activator, and NO-containing systems, it was found that intracellular superoxide could scavenge NO and shift the sGC redox equilibrium while extracellular superoxide reacted with NO only outside the cell [54]. ROS-mediated shift of the sGC heme redox equilibrium towards the Fe 3+ state greatly reduced the activity of the signaling pathway [58]. While many of these studies were conducted in rats [53–55], increased oxidative stress due to a peroxyl radical generator in isolated monkey coronary arteries also resulted in a disruption in the sGC redox state, demonstrating the importance of heme regulation in nonhuman primates as well [58].…”

Section: Heme Regulation Of Sgcmentioning

confidence: 99%

Redox regulation of soluble guanylyl cyclase

et al. 2018

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The nitric oxide/soluble guanylyl cyclase (NO-sGC) signaling pathway regulates the cardiovascular, neuronal, and gastrointestinal systems. Impaired sGC signaling can result in disease and system-wide organ failure. This review seeks to examine the redox control of sGC through heme and cysteine regulation while discussing therapeutic drugs that target various conditions. Heme regulation involves mechanisms of insertion of the heme moiety into the sGC protein, the molecules and proteins that control switching between the oxidized (Fe) and reduced states (Fe), and the activity of heme degradation. Modifications to cysteine residues by S-nitrosation on the α1 and β1 subunits of sGC have been shown to be important in sGC signaling. Moreover, redox balance and localization of sGC is thought to control downstream effects. In response to altered sGC activity due to changes in the redox state, many therapeutic drugs have been developed to target decreased NO-sGC signaling. The importance and relevance of sGC continues to grow as sGC dysregulation leads to numerous disease conditions.

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Section: Heme Regulation Of Sgcmentioning

confidence: 99%

Redox regulation of soluble guanylyl cyclase

et al. 2018

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“… 52 Alternative mechanisms of soluble GC activation by oxidant molecules described in other cell types are likely to underlie the effect of platelet NOXs on intracellular cGMP. 53 , 54 …”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis

Vara

Mailer

Tarafdar

et al. 2021

ATVB

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Objective: Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1 −/− /NOX2 −/− /NOX4 −/− ), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo. Approach and Results: 3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP—a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride–driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal. Conclusions: This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.

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“…Though, we observed a significant decrease in aortic soluble guanylate cyclase (sGC) subunits being accompanied by the reduced phosphorylation of VASP at Ser239, a surrogate marker of PKG [36]. sGC is important in NO signaling, commonly referred as the “NO receptor.” However, sGC is an enzyme which is highly sensitive to redox environment, as it is shown that elevated oxidative stress can change its redox state and lead to its deactivation [37]. It is known that sGC is affected by oxidation/loss of the sGC heme, oxidation, or nitrosation of cysteine residues and phosphorylation [38, 39].…”

Section: Discussionmentioning

confidence: 99%

T Cell-Derived IL-17A Induces Vascular Dysfunction via Perivascular Fibrosis Formation and Dysregulation of^⋅NO/cGMP Signaling

Schüler

Efentakis

Wild

et al. 2019

Oxidative Medicine and Cellular Longevity

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Aims. The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation. Methods and Results. Chronic IL-17A overexpression in T cells (CD4-IL-17Aind/+ mice) resulted in elevated reactive oxygen species in the peripheral blood and a significant vascular dysfunction compared to control mice. The vascular dysfunction seen in the CD4-IL-17Aind/+ mice was only accompanied by a modest and nonsignificant accumulation of inflammatory cells within the vessel wall. Therefore, infiltrating myeloid cells did not serve as an explanation of the vascular dysfunction seen in a chronic IL-17A-driven mouse model. In addition to vascular dysfunction, CD4-IL-17Aind/+ mice displayed vascular fibrosis with highly proliferative fibroblasts. This fibroblast proliferation was induced by exposure to IL-17A as confirmed by in vitro experiments with primary murine fibroblastic cells. We also found that the ⋅NO/cGMP pathway was downregulated in the vasculature of the CD4-IL-17Aind/+ mice, while levels of protein tyrosine kinase 2 (PYK2), an oxidative stress-triggered process associated with T cell activation, were upregulated in the perivascular fat tissue (PVAT). Conclusions. Our data demonstrate that T cell-derived IL-17A elicits vascular dysfunction by mediating proliferation of fibroblasts and subsequent vascular fibrosis associated with PYK2 upregulation.

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Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Cited by 18 publications

References 44 publications

Redox regulation of soluble guanylyl cyclase

Redox regulation of soluble guanylyl cyclase

NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis

T Cell-Derived IL-17A Induces Vascular Dysfunction via Perivascular Fibrosis Formation and Dysregulation of^⋅NO/cGMP Signaling

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Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Cited by 18 publications

References 44 publications

Redox regulation of soluble guanylyl cyclase

Redox regulation of soluble guanylyl cyclase

NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis

T Cell-Derived IL-17A Induces Vascular Dysfunction via Perivascular Fibrosis Formation and Dysregulation of⋅NO/cGMP Signaling

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T Cell-Derived IL-17A Induces Vascular Dysfunction via Perivascular Fibrosis Formation and Dysregulation of^⋅NO/cGMP Signaling