Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation

Robichaux

et al. 2016

Sci Rep

Vascular smooth muscle cell (VSMC) activation in response to injury plays an important role in the development of vascular proliferative diseases, including restenosis and atherosclerosis. The aims of this study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular remodeling. In a mouse carotid artery ligation model, genetic knockdown of the Epac1 gene led to a significant reduction in neointima obstruction in response to vascular injury. Pharmacologic inhibition of Epac1 with an Epac specific inhibitor, ESI-09, phenocopied the effects of Epac1 null by suppressing neointima formation and proliferative VSMC accumulation in neointima area. Mechanistically, Epac1 deficient VSMCs exhibited lower level of PI3K/AKT signaling and dampened response to PDGF-induced mitochondrial fission and reactive oxygen species levels. Our studies indicate that Epac1 plays important roles in promoting VSMC proliferation and phenotypic switch in response to vascular injury, therefore, representing a therapeutic target for vascular proliferative diseases.

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury

Robichaux

et al. 2016

Sci Rep

“…The same group recently extended their observation in vivo showing that vascular injury-induced intimal thickening was significantly inhibited in EPAC1-deleted mice. 72 The reasons for these discrepancies are unclear but may involve some species differences.…”

Section: Regulation Of the Vsmc Proliferation And Migrationmentioning

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

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...

Epac activation inhibits IL-6-induced cardiac myocyte dysfunction

et al. 2016

Self Cite

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.