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Trends Pharmacol Sci. 2014 Aug;35(8):404-13. doi: 10.1016/j.tips.2014.05.003. Epub 2014 Jun 16.

Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond.

Author information

1
Pharmacology, Toxicology, and Clinical Pharmacy, Institute of Pharmacy, Universität Tübingen, Tübingen, Germany. Electronic address: robert.lukowski@uni-tuebingen.de.
2
Department of Medicine, University of Cambridge, Cambridge, UK.
3
Department of Pharmacology, University of Washington, Seattle, WA, USA.
4
Forschergruppe 923, Technische Universität München, Munich, Germany. Electronic address: franz.hofmann@mytum.de.

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.

KEYWORDS:

cGMP-dependent protein kinase type I; cardiomyopathy; guanylyl cyclases; nitric oxide; phosphodiesterase 5; protein kinase G

PMID:
24948380
DOI:
10.1016/j.tips.2014.05.003
[Indexed for MEDLINE]

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