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

Abstract

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.

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

“…The results of these studies demonstrate that the migratory and invasive response of VSMCs to PDGF is greatly reduced in the absence of EPAC1, although cAMP and PKA activity is unaltered (502,1088). The suppressed migration of EPAC1-null VSMCs was investigated by Kato and colleagues, demonstrating perturbation of cytosolic Ca 2ϩ release and subsequent dephosphorylation of cofilin in response to PDGF (225,502,1035).…”

“…Nevertheless, several recent papers have demonstrated that mitochondrial EPAC1 plays important roles in various physiological and pathophysiological conditions. For instance, EPAC1 is implicated in regulation of mitochondrial fission/fusion dynamics and in promoting VSMC prolifera-tion during neointima formation in response to vascular injury (1088). Another study by Brenner and colleagues (1100) suggests that EPAC1 could act as a key effector for mitochondrial cAMP by reducing mitochondrial Ca 2ϩ entry, stabilizing mitochondrial membrane potential, and inhibiting apoptosis in cardiomyocytes.…”

“…Two recent investigations focused on the role of EPAC1 in vascular disease to further build a strong case for the cAMP effector in the development of neointimal hyperplasia and potentially define a valuable therapeutic target (502,1088).…”

“…Both in vivo and ex vivo experiments demonstrate that deletion of EPAC1 reduces mitogenic signaling in VSMCs and neointima areas. Investigating PDGF-induced proliferative pathways revealed that although the MAPK pathway was unaltered by deletion of EPAC1, activation of the PI3K/ Akt pathway was attenuated in the absence of EPAC1 (1088). Indeed, drug-eluting stents coated with rapamycin to inhibit mTOR downstream of Akt are effective strategies to reduce restenosis rates in the clinic (735,739).…”

Structure-activity relationships of 2-substituted phenyl- N -phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)

“…A number of studies have revealed that EPAC proteins are critically involved in a variety of human diseases such as cancer, inflammation, bacterial and viral infections, central nervous system disorders, energy homeostasis and obesity, and cardiac functions. 8–14 …”