title: Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling.
abstract: Analyses of several mouse models imply that the phosphodiesterase 5 (PDE5) inhibitor sildenafil (SIL), via increasing cGMP, affords protection against angiotensin II (Ang II)-stimulated cardiac remodeling. However, it is unclear which cell types are involved in these beneficial effects, because Ang II may exert its adverse effects by modulating multiple renovascular and cardiac functions via Ang II type 1 receptors (AT1Rs). To test the hypothesis that SIL/cGMP inhibit cardiac stress provoked by amplified Ang II/AT1R directly in cardiomyocytes (CMs), we studied transgenic mice with CM-specific overexpression of the AT1R under the control of the α-myosin heavy chain promoter (αMHC-AT1R(tg/+)). The extent of cardiac growth was assessed in the absence or presence of SIL and defined by referring changes in heart weight to body weight or tibia length. Hypertrophic marker genes, extracellular matrix-regulating factors, and expression patterns of fibrosis markers were examined in αMHC-AT1R(tg/+) ventricles (with or without SIL) and corroborated by investigating different components of the natriuretic peptide/PDE5/cGMP pathway as well as cardiac functions. cGMP levels in heart lysates and intact CMs were measured by competitive immunoassays and Förster resonance energy transfer. We found higher cardiac and CM cGMP levels and upregulation of the cGMP-dependent protein kinase type I with AT1R overexpression. However, even a prolonged SIL treatment regimen did not limit the progressive CM growth, fibrosis, or decline in cardiac functions in the αMHC-AT1R(tg/+) model, suggesting that SIL does not interfere with the pathogenic actions of amplified AT1R signaling in CMs. Hence, the cardiac/noncardiac cells involved in the cross-talk between SIL-sensitive PDE activity and Ang II/AT1R still need to be identified.
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Julia
authors.initials: J
authors.lastname: Straubinger
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Verena
authors.initials: V
authors.lastname: Schöttle
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Nadja
authors.initials: N
authors.lastname: Bork
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Hariharan
authors.initials: H
authors.lastname: Subramanian
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Dünnes
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Michael
authors.initials: M
authors.lastname: Russwurm
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.).
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.) robert.lukowski@uni-tuebingen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D010879:Piperazines; D011687:Purines; D044140:Receptor, Angiotensin, Type 1; D013449:Sulfonamides; D000804:Angiotensin II; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP