Nature Medicine
11, 214 - 222 (2005)
Published online: 23 January 2005; | doi:10.1038/nm1175
Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyEiki Takimoto1, 5, Hunter C Champion1, 5, Manxiang Li1, 5, Diego Belardi1, Shuxun Ren2, E Rene Rodriguez3, Djahida Bedja4, Kathleen L Gabrielson4, Yibin Wang2
& David A Kass11
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Ross 835, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. 2
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Room BH 569, CHS, 650 Charles E. Young Drive, Los Angeles, California 90095, USA. 3
Department of Pathology, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 4
Division of Comparative Medicine, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to David A Kass dkass@jhmi.eduSustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
