PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways

Kwak, Hyun-Jeong; Choi, Hyun‐Chul; Chung, Kyung‐Sook; Lim, Hyun-Joung; Park, Hyun-Young

doi:10.1016/j.cellsig.2007.12.011

Cited by 75 publications

(48 citation statements)

References 48 publications

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“…The effect of cAMP on the PI3Kinase pathway has been described to differ between cell types as the two main effectors of cAMP: protein kinase A and EPAC have been reported to have opposing effects on the pathway (Smith et al 2005, Chen et al 2007, Kwak et al 2008, Baviera et al 2010. In the present set of experiments, the effect of cAMP seems to be inhibitory on the FOXO3A/AKT1 phosphorylation.…”

Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 48%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15-26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation. Reproduction (2015) 150 11-20

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Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 48%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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“…Several studies have identified a role for cAMP-GEF signaling in cell survival (12,33,34,56). In rodent hepatocytes activation of cAMP-GEF protects against Fas, TNF-␣, and bile acid-induced apoptosis (12,61).…”

Section: Discussionmentioning

confidence: 99%

“…cAMP-GEFs catalyze the formation of the active GTP-bound form of the small GTPases, Rap. Over the last 10 years since their discovery the cAMP-GEF signaling pathways have been shown to regulate a growing array of cellular functions including integrin-mediated cell adhesion, gap junction formation, calcium-mediated exocytosis, and cell survival (12,26,33,34,41,56,59).…”

mentioning

confidence: 99%

cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

Gates¹,

Hohenester²,

Anwer³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…3C). This process likely underpins observations of various investigators indicating that EPAC can elicit Akt/PKB activation (29,30).…”

Section: Epac Activation Triggers the Phosphorylation Of Pkb/akt At Smentioning

confidence: 99%

EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation

Huston

Lynch²,

Mohamed

et al. 2008

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

116

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We identify a compartmentalized signaling system that identifies a functional role for the GTP exchange factor, exchange protein activated by cAMP (EPAC) coupled to Rap2 in the nucleus. In this system, cAMP regulates the nuclear/cytoplasmic trafficking of DNA-dependent protein kinase (DNA-PK), a critical kinase that acts to repair double-stranded breaks (DSBs) in damaged DNA and to phosphorylate the cell survival kinase, PKB/Akt. Intersecting regulatory inputs for cAMP employ EPAC to transduce positive effects, namely the Rap2-dependent nuclear exit and activation of DNA-PK, whereas protein kinase A (PKA) provides the negative input by antagonizing these actions. We identify this as a compartmentalized regulatory system where modulation of cAMP input into the stimulatory, EPAC and inhibitory, PKA intersecting arms is provided by spatially discrete, cAMP degradation systems. The distribution of DNA-PK between nuclear and cytoplasmic compartments can thus potentially be influenced by relative inputs of cAMP signaling through the EPAC and PKA pathways. Through this signaling system EPAC activation can thereby impact on the Ser-473 phosphorylation status of PKB/Akt and the repair of etoposide-induced DSBs.phosphodiesterase ͉ PDE4 ͉ rolipram ͉ PKB ͉ Akt

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PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways

Cited by 75 publications

References 48 publications

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation

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