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Research ArticleCardiovascular

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling

Julia Straubinger, Verena Schöttle, Nadja Bork, Hariharan Subramanian, Sarah Dünnes, Michael Russwurm, Meinrad Gawaz, Andreas Friebe, Mona Nemer, Viacheslav O. Nikolaev and Robert Lukowski
Journal of Pharmacology and Experimental Therapeutics September 2015, 354 (3) 406-416; DOI: https://doi.org/10.1124/jpet.115.226092
Julia Straubinger
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.)
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Verena Schöttle
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.)
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Nadja Bork
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.)
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Hariharan Subramanian
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.)
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Sarah Dünnes
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.)
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Michael Russwurm
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.)
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Meinrad Gawaz
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.)
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Andreas Friebe
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.)
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Mona Nemer
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.)
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Viacheslav O. Nikolaev
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.)
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Robert Lukowski
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.)
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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-AT1Rtg/+). 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-AT1Rtg/+ 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-AT1Rtg/+ 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.

Footnotes

    • Received May 20, 2015.
    • Accepted July 7, 2015.
  • This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Research Unit 2060 “cGMP signaling in cell growth and survival” with grants to R.L., A.F., and V.O.N. and by the Elite Programme financed by the Landesstiftung Baden-Württemberg (to R.L.). The DFG-funded Klinische Forschergruppe (KFO274) contributed to parts of the study.

  • dx.doi.org/10.1124/jpet.115.226092.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 354 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 354, Issue 3
1 Sep 2015
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Research ArticleCardiovascular

SIL/cGMP and Amplified AT1R Signaling in Cardiomyocytes

Julia Straubinger, Verena Schöttle, Nadja Bork, Hariharan Subramanian, Sarah Dünnes, Michael Russwurm, Meinrad Gawaz, Andreas Friebe, Mona Nemer, Viacheslav O. Nikolaev and Robert Lukowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2015, 354 (3) 406-416; DOI: https://doi.org/10.1124/jpet.115.226092

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Research ArticleCardiovascular

SIL/cGMP and Amplified AT1R Signaling in Cardiomyocytes

Julia Straubinger, Verena Schöttle, Nadja Bork, Hariharan Subramanian, Sarah Dünnes, Michael Russwurm, Meinrad Gawaz, Andreas Friebe, Mona Nemer, Viacheslav O. Nikolaev and Robert Lukowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2015, 354 (3) 406-416; DOI: https://doi.org/10.1124/jpet.115.226092
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