title: Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway.
abstract: Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI (P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice (P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment (P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment (P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase (P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.
authors.affiliation: Div. of Cardiology, Box 980204, Virginia Commonwealth Univ., 1101 E. Marshall St., Rm. 7-020A, Richmond, VA 23298, USA.
authors.forename: Vinh Q
authors.initials: VQ
authors.lastname: Chau
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000503:physiopathology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D013450:Sulfones; D051028:bcl-2-Associated X Protein; D000068677:Sildenafil Citrate; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein