PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production

García-Morales, Verónica; Cuíñas, Andrea; Elíes, Jacobo; Campos‐Toimil, Manuel

doi:10.1016/j.vph.2014.01.004

Cited by 39 publications

(30 citation statements)

References 44 publications

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“…Although these mechanisms within the smooth muscle cells are important to the relaxation state, the presence of an intact endothelium is also found to be required in achieving maximal relaxation by EPAC activation. In support of this relaxation state, both PKA and EPAC were determined to activate endothelial nitric oxide synthase (eNOS) increasing nitric oxide (NO) production by 14 and 15%, respectively, and leading to enhanced relaxation of the overlying muscle (336,878). Supporting this function, Rap1B-null mice exhibit reduced vascular endothelial growth factor (VEGF) stimulation of eNOS and subsequent NO generation promoting the development of hypertension in the model (577).…”

Section: Vascularmentioning

confidence: 99%

“…Interestingly, during relaxation of vascular smooth muscles, EPAC activation is implicated in reduction of cytosolic Ca 2ϩ by increasing BK Ca channels activity (878) or slowly leaking cytosolic Ca 2ϩ from the SR to reduce the SR load (208), consequently hyperpolarizing the membrane and attenuating contractile states, respectively. EPAC activation is also associated with the activation of eNOS, along with PKA, in endothelial cells to produce NO and induce relaxation of nearby muscle (336,878). During stress however, EPAC/Rap1 initiates a RhoA-dependent mechanism to translocate ␣ 2c -adrenoreceptors to the cell surface and induce vasoconstriction (182,183,471,472,737).…”

Section: Contraction/relaxationmentioning

confidence: 99%

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Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

162

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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Section: Vascularmentioning

confidence: 99%

Section: Contraction/relaxationmentioning

confidence: 99%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

162

226

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“…[59][60][61] In addition, EPAC-induced arterial smooth muscle relaxation may be a consequence of the activation of endothelial nitric oxide synthase and the subsequent production of nitric oxide, a potent vasodilatator molecule in endothelial cells ( Figure 5). 62 Of particular importance, activation of EPAC-Rap1 signaling lowers VSMC contractility via the inhibition of the small GTPase RhoA activity, a master regulator of VSMC contraction and the dephosphorylation of myosin light chain ( Figure 5). 55,56 Conversely, in microvascular smooth muscle cells EPAC stimulates RhoA activity to increase the expression of functional α2C-ARs that mediate constriction of small blood vessels.…”

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

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C yclic adenosine 3′,5′-monophosphate (cAMP) is one of the most studied signaling molecules that plays a critical role in cellular responses to extracellular stimuli in the cardiovascular system. It controls a wide range of biological effects, including cell proliferation, differentiation, and apoptosis. 1 cAMP is produced from ATP by transmembrane adenylyl cyclase on activation of Gs-coupled G protein-coupled receptors. 2In addition, soluble adenylyl cyclase is a second intracellular source of cAMP and can be activated by divalent cations in various subcellular compartments.3 The intracellular level of cAMP depends not only on its production by adenylyl cyclase but also its degradation by a large family of cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5′-AMP. 4 PDEs are key actors in limiting the spread of cAMP and seem critical for the formation of dynamic microdomains that confer specific response to various hormones. 4 Besides specialized membrane structures that may also limit cAMP diffusion, A-kinase anchoring proteins function to tether cAMP effectors and PDEs enzymes into defined cellular compartments and, therefore, maintain localized pools of cAMP to control the cellular actions of the second messenger. 5Until recently, the intracellular effects of cAMP were attributed to the activation of protein kinase A (PKA) and cyclic nucleotide-gated ion channels. In 1998, a family of novel cAMP effector proteins named exchange proteins directly activated by cAMP (EPACs) was discovered. 6,7 The EPAC protein family is composed of EPAC1 and EPAC2, which act as guanine-nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2, and function in a PKA-independent manner. 6,7 On binding to cAMP, EPAC promotes the exchange of GDP for GTP, thereby inducing the activation of the small G protein Rap.8 In contrast, Rap-GTPase-activating proteins enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. 9The cycling of Rap between its inactive and active states provides a mechanism to regulate the binding to effector proteins.The discovery of EPAC proteins has broken the dogma surrounding cAMP and PKA, and uncovered new perspectives for the understanding of cAMP signaling in the cardiovascular system. The functions of these cAMP-sensitive GEFs in various subcellular compartments and cellular contexts are currently being unraveled, but given the availability of EPAC-specific ligands and engineered mouse models, a large body of evidence indicates that EPAC proteins are involved in multiple biological actions of cAMP, such as cardiac hypertrophy and vascular inflammation. In this review, after a description of EPAC protein structures and mechanism of activation, we discuss recent advances in the discovery of novel pharmacological modulators of EPAC (Figure 1). We provide an overview of the roles of EPAC proteins, their signalosome and compartmentation in cardiovascular function and diseases. We also discuss the therapeutic potential of EPAC ligands in the t...

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“…As mentioned before endothelium dysfunction is caused by an imbalance between vasoconstrictor and vasodilator molecules, and between pro-atherogenic and anti-coagulant states [14] . This pathological condition is characterized by one or more of the following features: impaired NO bioavailability, increased oxidative stress, enhanced cell turnover, increased production of growth factor, over-expression of adhesion molecules and inflammatory genes, hemodynamic deregulation and increased permeability of the cell layer [15] .…”

Section: Endothelium Dysfunction and Cardiovascular Diseases: Role Ofmentioning

confidence: 94%

Nutraceuticals and cardiovascular risk: potential role of EPCs modulation

Russo

Lucchesi

Longo

et al. 2015

Stem Cell Transl Investig

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According to WHO cardiovascular diseases (CVDs) are the first cause of death in the world: more people die annually from CVDs than from any other cause. Vascular endothelium plays a pivotal role in the onset and progression of these pathologies and cardiovascular risk factors are frequently associated to the levels of endothelial progenitor cells (EPCs), bone marrow-derived circulating progenitors for the endothelial lineage. Since EPCs not only preserve vascular endothelium homeostasis, but might directly participate to re-endothelization and neovascularization, these cells represent an emerging protagonist in vascular competency and as such a cell model of great interest. An unhealthy diet is one of the main cardiovascular risk factor, while there is a great interest in the potential protective effects of "nutraceuticals", food-derived compounds that exert beneficial effects on human and animal health. The characterization of the endothelial effects of different nutraceuticals may provide fresh insights into their potential role in CVDs prevention. Several studies have already showed the protective effects of natural antioxidants on EPCs levels and functionality; some examples are resveratrol, catechin and folic acid. Fermentation has recently shown interesting roles in cardiovascular prevention since this process gave origin to a new class of foods, rich in bioactive compounds, the fermented foods. Consumption of fermented legumes and cereals, but also fermented beverages (such as beer and wine) was found to protect endothelial function through both lipid-lowering, as well anti-inflammatory and antioxidative mechanisms. Little is known about the effects of fermentation-derived nutraceuticals on EPCs. Given the important role of this cardiovascular biomarker, further analysis in this field can improve opportunities for CVDs prevention and treatment. Vascular endothelium and EPCs: new insightsFor many years vascular endothelium has been considered a mere physical barrier between blood and underlying tissues; recent studies have demonstrated new and interesting roles of endothelium in vascular health [1] .Endothelial cells composing this monolayer have therefore paracrine, endocrine and autocrine functions, by secreting several factors with vasodilatory and antiproliferative effects, such as endothelium-derived hyperpolarization factor (EDHF), nitric oxide (NO) and prostacyclin (PGI 2 ), and others inducing vasoconstrictor response, for instance endothelin-1 (ET-1), angiotensin II and reactive oxygen species (ROS) [2] . These evidences make the vascular endothelium a multifunctional unit that regulates vascular homeostasis by REVIEW

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PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production

Cited by 39 publications

References 44 publications

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Nutraceuticals and cardiovascular risk: potential role of EPCs modulation

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