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Cyclic AMP reverses the pro‐fibrogenic phenotype of cardiac myofibroblasts (850.3)
Author(s) -
Aroonsakool Nakon,
Yokoyama Utako,
Lu David,
Patel Hemal,
Insel Paul
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.850.3
Subject(s) - forskolin , adenylyl cyclase , activator (genetics) , myofibroblast , endocrinology , medicine , gene isoform , phosphodiesterase , fibrosis , fibroblast , phosphodiesterase inhibitor , chemistry , phenotype , extracellular matrix , intracellular , microbiology and biotechnology , biology , biochemistry , receptor , in vitro , enzyme , stimulation , gene
Previous data have shown that increased cellular levels of cyclic AMP (cAMP) can prevent the transformation of cardiac fibroblast (CFs) into pro‐fibrogenic myofibroblasts (MyoFbs), a transformation that precedes increased extracellular matrix deposition and cardiac fibrosis. We have now investigated two additional roles for cAMP: 1) contribution to the MyoFb phenotype and 2) reversal of the MyoFb phenotype. We found that MyoFbs have lower cAMP content than do CFs, and in addition, have decreased mRNA and protein expression of isoforms of adenylyl cyclase (AC), including AC5 and AC6, the two major AC isoforms, and increased expression of several phosphodiesterase isoforms. Incubation of primary isolates of adult rat CFs with a pro‐fibrotic stimulus, TGFβ1 (10ng/mL, 48hr), prominently increases mRNA and protein expression of collagen Iα1, Iα2, III, α‐smooth muscle actin, plasminogen activator inhibitor‐1 and cellular contractile state. All these hallmarks of the fibrogenic state were reversed in MyoFbs incubated with 10µM forskolin (a direct AC activator). Furthermore, incubation with N6‐Phe‐cAMP (a PKA selective analog) also reversed the pro‐fibrogenic state. We conclude that MyoFbs have a lower level of cAMP and that increasing cAMP content can reverse their pro‐fibrotic state. Approaches to increase cAMP in MyoFbs may provide a means to treat cardiac fibrosis. Grant Funding Source : NIH