Epac is an integrator of pro‐and anti‐fibrotic signals in cardiac fibroblasts

Abstract

Cyclic AMP (cAMP) regulates many biological processes but its role in tissue remodeling is not well understood. Actions of cAMP occur via protein kinase A (PKA) and by Exchange protein activated by cAMP (Epac). We hypothesized that Epac and PKA play distinct roles in cAMP‐mediated effects on cardiac fibroblasts (CF), which regulate repair and remodeling in the heart. We found that the Epac activator, Me‐cAMP, stimulated, while the PKA activator, Phe‐cAMP, inhibited CF migration, as assessed by a Boyden chamber method. siRNA‐mediated disruption of Epac1 blocked agonist‐induced migration of CF while a PKA inhibitor enhanced migration. Activation of either Epac or PKA inhibited collagen I and III mRNA expression. Pro‐fibrogenic agonists (TGFβ1, angiotensin II and endothelin) decreased Epac1 mRNA expression and Epac‐induced migration. Overexpression of Epac1 inhibited TGFβ1‐induced collagen synthesis and Epac1 protein expression decreased at the border zone of rats with myocardial infarction. In summary, 1) Epac promotes while PKA inhibits migration of CF; 2) Epac1 expression is decreased by pro‐fibrotic agonists and by myocardial infarction and 3) Increased expression of Epac1 decreases collagen synthesis. Thus, Epac1 appears to integrate pro‐and anti‐fibrotic signals in the heart.This work was supported by grants from NIH (2P01HL066941‐060005), AHA, VA and the Ellison Medical Foundation.