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Modulation of growth factor induced MAPK activation by a tumor suppressor in rat cardiac fibroblasts; Implications in heart failure
Author(s) -
Gupta Madhu,
Chandrashekar Deepa,
Kazakos Yianna
Publication year - 2006
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.20.4.a547
Subject(s) - mapk/erk pathway , heart failure , suppressor , cancer research , microbiology and biotechnology , modulation (music) , medicine , chemistry , endocrinology , biology , signal transduction , physics , cancer , acoustics
DOC‐2 is a negative regulator of growth in prostrate carcinoma. This study tested if DOC‐2 will alter MAP kinase activation and collagen expression induced by angiotensin II (A II) and phorbol esters (TPA) in cardiac fibroblasts. Methods Fibroblasts were obtained from neonatal rat hearts, cultured for 48 hrs, infected with adenovirus (Ad) or Ad‐DOC‐2 for 72 hrs. Following overnight serum starvation, cells were treated with A II (1 uM) or TPA (0.1uM) for 2,5,10, and 20 min (Group1), for 15hr (Group2), or MEK1/2 inhibitor PD98059 (10uM) for 8 hrs followed by A II for 15 hr (Group3). Protein lysates were prepared and analyzed for pERK, total ERK and Type I collagen by Western using specific antibodies. Results GroupI: TPA or A II resulted in immediate induction of pERK (at 2 min) with maximal effect at 5 min (for A II) and 10 min (for TPA). The effect was inhibited by Ad‐Doc‐2. Group2 and 3: A II and TPA for 15 hr increased typeI collagen by 66% and 20% respectively. This induced collagen expression was inhibited by Ad‐Doc‐2 and by PD98059. Ad‐control had no effect. Conclusions DOC‐2 inhibits growth factor‐induced activation of pERK and represses collagen expression. Inhibition of pERK alone represses collagen synthesis. Thus, DOC‐2 may help modulate cardiac fibrosis during heart failure.