EPAC expression and function in cardiac fibroblasts and myofibroblasts

• Published in: Toxicology and applied pharmacology 2013-10, Vol.272 (2), p.414-422
• Main Authors: Olmedo, Ivonne, Muñoz, Claudia, Guzmán, Nancy, Catalán, Mabel, Vivar, Raúl, Ayala, Pedro, Humeres, Claudio, Aránguiz, Pablo, García, Lorena, Velarde, Victoria, Díaz-Araya, Guillermo
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adhesion; AMP; Animals; Animals, Newborn; Biological and medical sciences; Cardiac fibroblast and myofibroblast; Cardiovascular system; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Movement - drug effects; Cell Movement - physiology; Cells, Cultured; COLLAGEN; Collagen - biosynthesis; EPAC-1; FIBROBLASTS; Fibroblasts - drug effects; Fibroblasts - metabolism; GELS; GROWTH FACTORS; Guanine Nucleotide Exchange Factors - biosynthesis; Guanine Nucleotide Exchange Factors - physiology; HEALING; HEART; Heart Ventricles - cytology; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Medical sciences; Migration; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Pharmacology. Drug treatments; RATS; Rats, Sprague-Dawley; SYNTHESIS; TGF-beta1; Transforming Growth Factor beta1 - pharmacology; Ventricular Remodeling - physiology; WOUNDS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.06.022

In the heart, cardiac fibroblasts (CF) and cardiac myofibroblasts (CMF) are the main cells responsible for wound healing after cardiac insult. Exchange protein activated by cAMP (EPAC) is a downstream effector of cAMP, and it has been not completely studied on CF. Moreover, in CMF, which are the main cells responsible for cardiac healing, EPAC expression and function are unknown. We evaluated in both CF and CMF the effect of transforming growth factor β1 (TGF-β1) on EPAC-1 expression. We also studied the EPAC involvement on collagen synthesis, adhesion, migration and collagen gel contraction. Rat neonatal CF and CMF were treated with TGF-β1 at different times and concentrations. EPAC-1 protein levels and Rap1 activation were measured by western blot and pull down assay respectively. EPAC cellular functions were determined by adhesion, migration and collagen gel contraction assay; and collagen expression was determined by western blot. TGF-β1 through Smad and JNK significantly reduced EPAC-1 expression in CF, while in CMF this cytokine increased EPAC-1 expression through ERK1/2, JNK, p38, AKT and Smad3. EPAC activation was able to induce higher Rap1-GTP levels in CMF than in CF. EPAC and PKA, both cAMP effectors, promoted CF and CMF adhesion on fibronectin, as well as CF migration; however, this effect was not observed in CMF. EPAC but not PKA activation mediated collagen gel contraction in CF, while in CMF both PKA and EPAC mediated collagen gel contraction. Finally, the EPAC and PKA activation reduced collagen synthesis in CF and CMF. TGF-β1 differentially regulates the expression of EPAC in CF and CMF; and EPAC regulates differentially CF and CMF functions associated with cardiac remodeling. •TGF-β1 regulates EPAC-1 expression in cardiac fibroblast and myofibroblast.•Rap-1GTP levels are higher in cardiac myofibroblast than fibroblast.•EPAC-1 controls adhesion, migration and collagen synthesis in cardiac fibroblast.•PKA regulates collagen gel contraction in cardiac myofibroblast.