Activators of Epac proteins induce relaxation of isolated rat aorta

Sukhanova, I. F.; Кожевникова, Л. М.; Попов, Э. Г.; Podmareva, O. N.; Авдонин, П. В.

doi:10.1134/s0012496606060044

Cited by 17 publications

(16 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An earlier study reported 007-induced relaxation of intact rat aorta precontracted with noradrenalin or phenylephrine but concluded that the effects could be mediated via endothelial cells or SMCs (47). Our data are the first to report that activation of Epac leads to relaxation of SM Ca 2ϩ -sensitized force through activation of Rap1 accompanied by a fall in RhoA activity and a decrease in both MYPT1 phosphorylation at Thr-853 and RLC 20 phosphorylation.…”

Section: Discussionsupporting

confidence: 50%

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Zieba

Artamonov

Jin

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

This study reports a new mechanism of cAMP mediated relaxation of Ca2+sensitized force, in smooth muscle (SM) through Epac, a GTP exchange factor for the small GTPase Rap1 which results in suppression of RhoA activity. We find that Epac selective cAMP analogue, 8‐pCPT‐2′‐O‐Me‐cAMP (007), significantly reduced agonist‐induced contractile force, in both intact and permeabilized vascular, gut and airway SM. Responses to 007 were independent of PKA and PKG. Activation of Epac resulted in increased Rap1·GTP accompanied by a significant decrease in RhoA activity and reductions in phosphorylation of RLC20 and MLCP. Transcriptional regulation of SM α‐actin and SM22, known to be regulated by RhoA, was also significantly decreased by activation of Epac. Forskolin, the phosphodiesterase inhibitor IBMX and isoproterenol significantly increased Rap1·GTP in rat aortic SM cells. Over‐expression of wild‐type Epac but not dominant negative Epac1R279E increased Rap1 activation after 007 stimulation. LPA‐induced activation of RhoA activity was reduced by treatment with 007 in WT but not Rap1B null fibroblasts. All together, our findings show a novel signaling mechanism whereby activation of Epac via cAMP results in PKA independent, Rap1 dependent Ca2+ desensitization of force in SM.

show abstract

Section: Discussionsupporting

confidence: 50%

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Zieba

Artamonov

Jin

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Subsequently, cAMP transduces its effects in ASM cells via activation of protein kinase A (PKA) and/or the exchange protein activated by cAMP (Epac). Recent publications have demonstrated that both PKA and Epac are involved in cAMP-mediated contractile (Sukhanova et al, 2006;Cazorla et al, 2009;Metrich et al, 2009;Roscioni et al, 2010), proliferative (Haag et al, 2008;Huang et al, 2008;Kassel et al, 2008) and inflammatory (Roscioni et al, 2009;Scheibner et al, 2009;Xing and Birukova, 2010) responses in several cell types, including ASM cells. The functional impact of cAMP and its downstream effectors on ASM phenotype changes are mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

Roscioni

Dekkers

Prins

et al. 2010

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSE Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet‐derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo‐contractile phenotype, a process requiring activation of extracellular signal‐regulated kinase (ERK) and p70S6 Kinase (p70S6K). The effects of cAMP‐elevating agents on these processes is unknown. Here, we investigated the effects of cAMP elevation by prostaglandin E2 (PGE2) and the activation of the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (Epac) on PDGF‐induced phenotype switching in bovine tracheal smooth muscle (BTSM).EXPERIMENTAL APPROACH Effects of long‐term treatment with the PGE2 analogue 16,16‐dimethyl‐PGE2, the selective Epac activator, 8‐pCPT‐2′‐O‐Me‐cAMP and the selective PKA activator, 6‐Bnz‐cAMP were assessed on the induction of a hypo‐contractile, proliferative BTSM phenotype and on activation of ERK and p70S6K, both induced by PDGF.KEY RESULTS Treatment with 16,16‐dimethyl‐PGE2 inhibited PDGF‐induced proliferation of BTSM cells and maintained BTSM strip contractility and contractile protein expression in the presence of PDGF. Activation of both Epac and PKA similarly prevented PDGF‐induced phenotype switching and PDGF‐induced activation of ERK. Interestingly, only PKA activation resulted in inhibition of PDGF‐induced phosphorylation of p70S6K.CONCLUSIONS AND IMPLICATIONS Our data indicate for the first time that both Epac and PKA regulated switching of ASM phenotype via differential inhibition of ERK and p70S6K pathways. These findings suggest that cAMP elevation may be beneficial in the treatment of long‐term changes in airway disease.

show abstract

“…In rat aortic smooth muscle cells, Epac inhibits ATP-sensitive K + -channels through Ca 2+ -dependent calcineurin (Purves et al, 2009), suggesting that Epac, in particular Epac1 being primarily expressed in vascular smooth muscle, controls vascular tone and blood flow. Indeed, specific activation of Epac induces relaxation of rat aorta (Sukhanova et al, 2006) and rabbit and rat pulmonary aorta (Murray et al, 2009b;Zieba et al, 2011) through downregulation of RhoA-dependent myosin light chain phosphatase phosphorylation (Zieba et al, 2011;Fig. 8B).…”

Section: Epac and The Vasculature 1 Epac And The Endothelial Barrmentioning

confidence: 99%

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

2013

View full text Add to dashboard Cite

Activators of Epac proteins induce relaxation of isolated rat aorta

Cited by 17 publications

References 14 publications

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

Contact Info

Product

Resources

About