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Mitigation of Heart Failure Progression with Sildenafil Involves Inhibition of RhoA/Rho‐Kinase Pathway
Author(s) -
Salloum Fadi N,
Chau Vinh Q,
Hoke Nicholas N,
Abbate Antonio,
Kukreja Rakesh C
Publication year - 2010
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.24.1_supplement.601.13
Subject(s) - sildenafil , rhoa , medicine , saline , cgmp specific phosphodiesterase type 5 , rho associated protein kinase , tunel assay , myocardial infarction , phosphodiesterase , ctgf , heart failure , cardiology , endocrinology , pharmacology , kinase , chemistry , signal transduction , receptor , enzyme , biochemistry , immunohistochemistry , growth factor
Chronic inhibition of phosphodiesterase‐5 (PDE‐5) with sildenafil after permanent occlusion of the left anterior descending coronary artery (LAD) limits ischemic heart failure (HF) in mice. We postulated that treatment with sildenafil beginning at 3 days post myocardial infarction (MI) would also attenuate HF through inhibition of RhoA/Rho kinase pathway. Adult male ICR mice with fractional shortening (FS) less than 25% at day 3 following permanent LAD ligation were treated with either saline (volume matched, ip, BID) or sildenafil (21 mg/kg, ip, BID) for 25 days. Echocardiography showed FS preservation and less left ventricular dilatation with sildenafil treatment versus saline at 7 and 28 days post‐MI (P<0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and TUNEL, respectively, were attenuated with sildenafil (P<0.05 vs. saline). Western blotting showed enhanced Bcl‐2/Bax ratio with sildenafil (P<0.05 vs. saline). Activity assay showed sildenafil‐mediated PKG activation 1 day after treatment (P<0.05 vs. sham and saline). Activation of PKG with sildenafil was associated with inhibition of Rho kinase (P<0.05), as compared to saline. Our findings show that chronic sildenafil treatment in mice with HF attenuates LV dysfunction independent of its infarct‐sparing effect by inhibiting the RhoA/Rho kinase pathway. This research was funded by NIH (HL51045, 79424 and 93685 to RCK).