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Nicorandil Ameliorates Myocardial Fibrosis by Inhibition of RhoA/Rho‐kinase Signaling in Infarcted Rats
Author(s) -
Lee TsungMing,
Yang ChenChia
Publication year - 2015
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.29.1_supplement.1045.1
Subject(s) - rhoa , fasudil , nicorandil , glibenclamide , rho associated protein kinase , myofibroblast , medicine , fibrosis , chemistry , pharmacology , ctgf , endocrinology , signal transduction , growth factor , biochemistry , receptor , diabetes mellitus
We have demonstrated that ATP‐sensitive potassium (K ATP ) channel agonists attenuated fibrosis. Since RhoA has been identified as an important mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of K ATP channel agonists were mediated via inhibition of the RhoA/RhoA‐kinase (ROCK) cascade. Wistar rats after induction of myocardial infarctionwere randomized to either vehicle, an agonist of K ATP channel nicorandil, an antagonist of K ATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hours after infarction and for 4 weeks. Post‐infarction was associated with increased cardiac fibrosis, as measured bySirius Red staining and hydroxyproline assay. RhoA/ROCK activation was observed after infarction by increasing RhoA localization from the cytosol to the membrane and phosphorylating the ROCK substrate. Nicorandil diminished myocardial fibrosis by inhibiting RhoA/ROCK activation, connective tissue growth factor expression and α‐smooth muscle actin‐positive myofibroblast infiltration. Fasudil showed similar antifibrotic effect of nicorandil. The beneficial effects of nicorandil were blocked by adding glibenclamide. However, glibenclamide can not abolish the attenuated fibrosis of fasudil, implying that RhoA/ROCK is a downstream effector of K ATP channel activation. Chronic treatment with nicorandil, initiated at 24 hours after infarction can expedite the attenuation of infarction‐induced myocardial fibrosis probably through inhibition of RhoA/ROCK‐dependent connective tissue growth factor independent of its infarct‐sparing effect.