The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

Abstract

The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs.

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

“…While Epac1 is ubiquitously expressed, Epac2 displays a more restrained tissue distribution and is mainly present in the brain and endocrine tissues [101]. In cardiovascular system, Epac1 is found in multiple cell types such as cardiomyocytes, endothelial cells, and cardiac fibroblasts [105][106][107]. Evidence accumulated over the last ten years indicates that Epac1 plays a crucial role in modulating several cardiomyocyte functions including contractility, action potential propagation, myofilament function, and cardiomyocyte adaptation to biomechanical or neurohumoral stress [105,108].…”

The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs)

“…The cyclic AMP sensor enzyme, EPAC1, is a logical drug target for vascular inflammation because its ligand-mediated activation suppresses a wide range of inflammatory actions [ [31] , [32] , [33] ]. EPAC1 and EPAC2 proteins [ 34 , 35 ] are cyclic AMP-regulated guanine nucleotide exchange factors (GEFs) that activate the Ras GTPase homologues, Rap1 and Rap2, independently of the classical route of cAMP signal transduction through protein kinase A (PKA).…”

“…EPAC1 and EPAC2 proteins [ 34 , 35 ] are cyclic AMP-regulated guanine nucleotide exchange factors (GEFs) that activate the Ras GTPase homologues, Rap1 and Rap2, independently of the classical route of cAMP signal transduction through protein kinase A (PKA). Rather, binding of cAMP to a specific cyclic nucleotide-binding domain (CNBD) induces a conformational change in EPAC proteins that relieves auto-inhibition of the catalytic GEF domain [ 33 ]. EPAC1 appears to be a central controller of anti-inflammatory processes in VECs [ 31 , 36 ].…”

EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K/eNOS-dependent manner during inflammation

“…Despite significant progress in the development of cAMP analogues as EPAC agonists 93 , the EPAC isoform selectivity of these cAMP analogues and their potential off-target effects on other molecules, such as cAMP phosphodiesterase, remain challenging 77,78 . ESA I942, the first identified non-cyclic nucleotide small molecule with agonist properties towards EPAC1, and very little agonist action towards EPAC2 or PKA 57,58 , has the potential to suppress proinflammatory cytokine signaling.…”

“…ESA I942, the first identified non-cyclic nucleotide small molecule with agonist properties towards EPAC1 showed very little agonist action towards EPAC2 or protein kinase A (PKA) 57,58 . While the concentration of I942 was among 5μM to 50μM, it had little influence on the viability of HUVECs ( Figure S2A).…”