title: Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis.
abstract: Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg ⋅ kg(-1) ⋅ d(-1)) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.
authors.affiliation: Forschergruppe 923, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany;
authors.forename: Enrico
authors.initials: E
authors.lastname: Patrucco
authors.affiliation: Forschergruppe 923, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany;
authors.forename: Katrin
authors.initials: K
authors.lastname: Domes
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain;
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggió
authors.affiliation: Forschergruppe 923, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany;
authors.forename: Anne
authors.initials: A
authors.lastname: Blaich
authors.affiliation: Lehrstuhl für Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Regensburg, 93055 Regensburg, Germany;
authors.forename: Jens
authors.initials: J
authors.lastname: Schlossmann
authors.affiliation: Lehrstuhl für Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Regensburg, 93055 Regensburg, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Desch
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280; and.
authors.forename: Sergei D
authors.initials: SD
authors.lastname: Rybalkin
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280; and franz.hofmann@mytum.de beavo@u.washington.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Beavo
authors.affiliation: Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.affiliation: Forschergruppe 923, Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany; franz.hofmann@mytum.de beavo@u.washington.edu.
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D005819:Genetic Markers; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D005819:Genetic Markers; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006152:Cyclic GMP
keywords: NO/cyclic GMP system; PDE; PKGI; cardiac failure; hypertension