cCMP and cUMP in Apoptosis: Concepts and Methods

Wolter, Sabine; Dittmar, Fanni; Seifert, Roland

doi:10.1007/164_2016_5007

Cited by 8 publications

(2 citation statements)

References 72 publications

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“…Cells infected with P. aeruginosa expressing a functional T3SS have been shown to upregulate CD95/CD95L, which—upon activation—induces apoptosis [ 30 ]. In addition, it has been shown that high intracellular concentrations of cUMP can stimulate apoptosis [ 31 , 32 , 33 ]. An excessive incidence of cell death in the lung leads to a breakdown of lung barrier integrity.…”

Section: Discussionmentioning

confidence: 99%

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

Kloth

Schirmer

Munder

et al. 2018

Toxins

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The effector protein Exotoxin Y (ExoY) produced by Pseudomonas aeruginosa is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear. Here, we used an acute airway infection model in mice to address the role of ExoY in lung infection. In infected lungs, a dose-dependent phenotype of infection with bacteria-expressing ExoY was mirrored by haemorrhage, formation of interstitial oedema in alveolar septa, and infiltration of the perivascular space with erythrocytes and neutrophilic granulocytes. Analyses of the infection process on the cellular and organismal level comparing infections with Pseudomonas aeruginosa mutants expressing either nucleotidyl cyclase-active or -inactive ExoY revealed differential cytokine secretion, increased prevalence of apoptosis, and a break of lung barrier integrity in mice infected with cyclase-active ExoY. Notably, of all measured cyclic nucleotides, only the increase of cyclic UMP in infected mouse lungs coincides temporally with the observed early pathologic changes. In summary, our results suggest that the nucleotidyl cyclase activity of ExoY can contribute to P. aeruginosa acute pathogenicity.

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Section: Discussionmentioning

confidence: 99%

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

Kloth

Schirmer

Munder

et al. 2018

Toxins

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“…Since the cyclic nucleotides cAMP and cGMP were wellcharacterized second messenger molecules regulating many intracellular processes, such as cell proliferation, migration (Wolter et al, 2017), we further explored whether Frontiers in Pharmacology frontiersin.org PRO20 inhibited pathological cardiac remodeling through modulating intracellular cAMP and cGMP levels. Upon Ang II stimulation in CFs and CMs, intracellular cAMP and cGMP levels were significantly decreased (Figures 5A-D).…”

Section: Pro20 Enhanced Intracellular Camp Levels and Attenuated Endo...mentioning

confidence: 99%

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling

et al. 2022

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Background: Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown.Materials and methods: Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling.Results: Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of In vivo experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. In vitro experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration.Conclusion: Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.

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cCMP and cUMP Across the Tree of Life: From cCMP and cUMP Generators to cCMP- and cUMP-Regulated Cell Functions

Seifert

2016

Non-Canonical Cyclic Nucleotides

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The cyclic purine nucleotides cAMP and cGMP are well-established second messenger molecules that are generated by distinct nucleotidyl cyclases (NCs) and regulate numerous cell functions via specific effector molecules. In contrast, the existence of the cyclic pyrimidine nucleotides cCMP and cUMP has been controversial for many years. The development of highly specific and sensitive mass spectrometry methods has enabled the unequivocal detection and quantitation of cCMP and cUMP in biological systems. These cNMPs occur broadly in numerous mammalian cell lines and primary cells. cCMP has also been detected in mouse organs, and both cCMP and cUMP occur in various developmental stages of the zebrafish Danio rerio. So far, the soluble guanylyl cyclase (sGC) and soluble adenylyl cyclase (sAC) have been identified as cCMP and cUMP generators. Dissociations in the expression patterns of sAC and sGC relative to cCMP and cUMP abundance may point to the existence of hitherto unidentified cCMP- and cUMP-generating NCs. The broad occurrence of cCMP and cUMP in vertebrates and the distinct cNMP patterns suggest specific roles of these cNMPs in the regulation of numerous cell functions.

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cCMP and cUMP in Apoptosis: Concepts and Methods

Cited by 8 publications

References 72 publications

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling

cCMP and cUMP Across the Tree of Life: From cCMP and cUMP Generators to cCMP- and cUMP-Regulated Cell Functions

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