title: Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond.
abstract: cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed.
authors.affiliation: Pharmacology, Toxicology, and Clinical Pharmacy, Institute of Pharmacy, Universität Tübingen, Tübingen, Germany. Electronic address: robert.lukowski@uni-tuebingen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: Sergei D
authors.initials: SD
authors.lastname: Rybalkin
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Beavo
authors.affiliation: Forschergruppe 923, Technische Universität München, Munich, Germany. Electronic address: franz.hofmann@mytum.de.
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D006331:Heart Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: cGMP-dependent protein kinase type I; cardiomyopathy; guanylyl cyclases; nitric oxide; phosphodiesterase 5; protein kinase G