title: Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo.
abstract: Sildenafil inhibits cyclic GMP-specific phosphodiesterase type-5A (PDE5A) and can prevent cardiac hypertrophy and left ventricular (LV) dysfunction in mice subjected to severe pressure-overload. The pathophysiological role of sildenafil in adverse remodeling in the hypertensive heart after chronic renin-angiotensin aldosterone system stimulation is unknown. Therefore, we studied the efficacy of the PDE5A inhibitor sildenafil for treating advanced cardiac hypertrophy and LV remodeling due to angiotensin (Ang)II-induced heart failure (HF) in vivo. C57BL6/J mice were subjected to AngII-induced cardiac hypertrophy for 3 weeks and cardiac dysfunction, cardiac inflammatory stress response, adverse remodeling as well as apoptosis were documented. Mice were subsequently treated with sildenafil (100 mg/kg/day) or placebo with delay of 5 days for treating AngII infusion-induced adverse events. Compared to controls, AngII infusion resulted in impaired systolic (dP/dt                 (max) -46 %, SV -16 %, SW -43 %, E                 (a) +51 %, EF -37 %, CO -36 %; p < 0.05) and diastolic (dP/dt                 (min) -36 %, LV end diastolic pressure +73 %, Tau +21 %, stiffness constant β +74 %; p < 0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased inflammatory response was also indicated by an increase in immune cell infiltration and apoptosis. Treatment with sildenafil led to a significant improvement in systolic and diastolic LV performance. This effect was associated with less LV hypertrophy, remodeling, cardiac inflammation and apoptosis. PDE5A inhibition with sildenafil may provide a new treatment strategy for cardiac hypertrophy and adverse remodeling in the hypertensive heart.
authors.affiliation: Department of Cardiology and Pneumology, Campus Benjamin Franklin (CBF), Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. dirk.westermann@web.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Diana
authors.initials: D
authors.lastname: Lindner
authors.forename: Kostantinos
authors.initials: K
authors.lastname: Savvatis
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.forename: Matthias
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents; D017209:Apoptosis / Q000187:drug effects; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy*; D006334:Heart Function Tests; D006830:Hydralazine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D014662:Vasoconstrictor Agents; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D016207:Cytokines; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013450:Sulfones; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D006830:Hydralazine; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse