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Soluble guanylyl cyclase mediates noncanonical nitric oxide signaling by nitrosothiol transfer under oxidative stress

ABSTRACT: Soluble guanylyl cyclase (GC1) is an α/β heterodimer producing cGMP when stimulated by nitric oxide (NO). The NO-GC1-cGMP pathway is essential to cardiovascular homeostasis but is disrupted by oxidative stress, which induces GC1 desensitization to NO by S-nitrosation (SNO) of its cysteines (C). We discovered that under these conditions, GC1-α subunit increases cellular S-nitrosation via transfer of its nitrosothiols to other proteins (transnitrosation). One of the SNO-targets was the oxidized form of the oxido-reductase Thioredoxin1 (oTrx1), which is unilaterally transnitrosated by GC1. GC1-αC610 was a major SNO-donor to oTrx1-C73. Because oTrx1 itself drives transnitrosation, we sought and identified several SNO-proteins targeted by both GC1 and oTrx1. Among them, transnitrosation of RhoA by SNO-GC1 requires oTrx1 as a nitrosothiol relay, suggesting a SNO-GC1→oTrx1→RhoA cascade. We showed that RhoA pathway, which is antagonized by the canonical NO-cGMP signaling, was alternatively inhibited by GC1-α-dependent S-nitrosation under oxidative conditions. We propose that some SNO-GC1’ functions are adaptive responses triggered by oxidation of the canonical NO-cGMP pathway

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

TISSUE(S): Atrial Cardiac Muscle Cell Action Potential, Fetal Cardiomyocyte

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Tong Liu

LAB HEAD: Annie Beuve

PROVIDER: PXD033105 | Pride | 2022-10-15

REPOSITORIES: Pride

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Soluble guanylyl cyclase mediates noncanonical nitric oxide signaling by nitrosothiol transfer under oxidative stress.

Cui Chuanlong C Wu Changgong C Shu Ping P Liu Tong T Li Hong H Beuve Annie A

Redox biology 20220802

Soluble guanylyl cyclase (GC1) is an α/β heterodimer producing cGMP when stimulated by nitric oxide (NO). The NO-GC1-cGMP pathway is essential for cardiovascular homeostasis but is disrupted by oxidative stress, which causes GC1 desensitization to NO by heme oxidation and S-nitrosation (SNO) of specific cysteines. We discovered that under these conditions, GC1-α subunit increases cellular S-nitrosation via transfer of nitrosothiols to other proteins (transnitrosation) in cardiac and smooth muscl ...[more]

PMID: 35961098

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Project description:Objectives and goals: The causes and molecular pathology of ovarian cancer are essentially unknown. However, it is generally understood that serous ovarian borderline tumors (SBOT) and well differentiated (WD) serous ovarian carcinomas (SC) have a similar tumorigenetic pathway, distinct from moderately (MD) and poorly differentiated (PD) SC. The aim of this study was to identify mRNAs differentially expressed between MD/PD SC, SBOT and superficial scrapings from normal ovaries (SNO),and to correlate these mRNAs with clinical parameters. Results: From the global gene expression analyses, thirty mRNAs differentially expressed between MD/PD SC, SBOT and SNO were selected and validated by RT-qPCR, verifying 21 mRNAs to be significantly differentially expressed (p<0.01). Of these, 13 mRNAs were differentially expressed in MD/PD SC compared with SNO (p<0.01) and were correlated with clinical parameters. VEGFA was significantly upregulated (FC=6.1, p=6.0x10-6), and correlated with progression-free survival (p=0.037). ZNF385B was significantly downregulated (FC=-130.5, p=1.2x10-7), and correlated with overall survival (p=0.03). An increased TPX2 (p=0.03) and FOXM1 (p=0.044) expression correlated with optimal normalization of serum CA125 after treatment. Furthermore, we present a common molecular pathway for MD/PD SC, including VEGFA, FOXM1, TPX2, BIRC5 and TOP2A, all significantly upregulated and interacting with TP53. Conclusions: We have identified 21 mRNAs differentially expressed (p<0.01) between MD/PD SC, SBOT and SNO. Thirteen were differentially expressed in MD/PD SC, including VEGFA and ZNF385B, correlating with survival, and FOXM1 and TPX2, correlating with normalization of serum CA125. By the use of oligonucleotid microarrays (Affymetrix U133 Plus 2.0 Arrays) differences in mRNA expression between eleven MD/PD SC, eight SBOT and four SNO samples were analyzed. Differentially expressed mRNAs were selected for validation by RT-qPCR in additional samples totaling 21 MD/PD SC, 13 SBOT and seven samples of SNO. Each mRNA was run in quadruple. The mRNAs differentially expressed in MD/PD SC compared with SNO were correlated with clinical parameters.

Dataset Information

Soluble guanylyl cyclase mediates noncanonical nitric oxide signaling by nitrosothiol transfer under oxidative stress

Publications

Soluble guanylyl cyclase mediates noncanonical nitric oxide signaling by nitrosothiol transfer under oxidative stress.

Similar Datasets

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