Journal ArticleDOI
Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy
Eiki Takimoto,Hunter C. Champion,Manxiang Li,Diego F. Belardi,Shuxun Ren,E. Rene Rodriguez,Djahida Bedja,Kathleen L. Gabrielson,Yibin Wang,David A. Kass +9 more
TLDR
It is shown 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.Abstract:
Sustained 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.read more
Citations
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Journal ArticleDOI
A Novel Paradigm for Heart Failure With Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation
Walter Paulus,Carsten Tschöpe +1 more
TL;DR: In this article, a new paradigm for heart failure with preserved ejection fraction (HFPEF) development is proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations.
Journal ArticleDOI
Regulation of cardiac hypertrophy by intracellular signalling pathways
TL;DR: Recent findings in genetically modified animal models implicate important intermediate signal-transduction pathways in the coordination of heart growth following physiological and pathological stimulation.
Journal ArticleDOI
Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use
Andrew T. Bender,Joseph A. Beavo +1 more
TL;DR: Basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed and how these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered.
Journal ArticleDOI
Genome-wide association: which do you want first: the good news, the bad news, or the good news?
TL;DR: The strength of the GWA is that it has the potential to identify genes of high genetic effect that were previously unsuspected as candidates, and is not biased by a priori assumptions based on prior observations of the phenotype.
Journal ArticleDOI
Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial
Margaret M. Redfield,Horng H. Chen,Barry A. Borlaug,Marc J. Semigran,Kerry L. Lee,Gregory D. Lewis,Martin M. LeWinter,Jean L. Rouleau,David A. Bull,Douglas L. Mann,Anita Deswal,Lynne W. Stevenson,Michael M. Givertz Elizabeth O Ofili,Michael M. Givertz Elizabeth O Ofili,Christopher M. O'Connor,G. Michael Felker,Steven R. Goldsmith,Bradley A. Bart,Steven McNulty,Jenny C. Ibarra,Grace Lin,Jae K. Oh,Manesh R. Patel,Raymond J. Kim,Russell P. Tracy,Eric J. Velazquez,Kevin J. Anstrom,Adrian F. Hernandez,Alice M. Mascette,Eugene Braunwald +29 more
TL;DR: Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.
References
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Journal ArticleDOI
A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy
Jeffery D. Molkentin,Jeffery D. Molkentin,Jianrong Lu,Christopher L. Antos,Bruce E. Markham,James A. Richardson,Jeffrey Robbins,Stephen R. Grant,Eric N. Olson +8 more
TL;DR: It is shown that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus.
Journal ArticleDOI
Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group.
Irwin Goldstein,Tom F. Lue,Harin Padma-Nathan,Raymond C. Rosen,William D. Steers,Pierre A. Wicker +5 more
TL;DR: Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction and is associated with improved erectile function in the dose-response study.
Journal ArticleDOI
Cardiac Hypertrophy: The Good, the Bad, and the Ugly
TL;DR: Recent insights into hypertrophic signaling are summarized, several novel antihypertrophic strategies are considered and modulation of myocardial growth without adversely affecting contractile function is increasingly recognized as a potentially auspicious approach in the prevention and treatment of heart failure.
Journal ArticleDOI
Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore
Magdalena Juhaszova,Dmitry B. Zorov,Dmitry B. Zorov,Suhn-Hee Kim,Suhn-Hee Kim,Salvatore Pepe,Salvatore Pepe,Qin Fu,Kenneth W. Fishbein,Bruce D. Ziman,Su Wang,Kirsti Ytrehus,Christopher L. Antos,Eric N. Olson,Steven J. Sollott +14 more
TL;DR: It is shown that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria.
Journal ArticleDOI
Hypertrophy of the heart: a new therapeutic target?
TL;DR: Observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy are summarized and signaling pathways that hold promise as potential targets for therapeutic intervention are focused on.
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Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial
Margaret M. Redfield,Horng H. Chen,Barry A. Borlaug,Marc J. Semigran,Kerry L. Lee,Gregory D. Lewis,Martin M. LeWinter,Jean L. Rouleau,David A. Bull,Douglas L. Mann,Anita Deswal,Lynne W. Stevenson,Michael M. Givertz Elizabeth O Ofili,Michael M. Givertz Elizabeth O Ofili,Christopher M. O'Connor,G. Michael Felker,Steven R. Goldsmith,Bradley A. Bart,Steven McNulty,Jenny C. Ibarra,Grace Lin,Jae K. Oh,Manesh R. Patel,Raymond J. Kim,Russell P. Tracy,Eric J. Velazquez,Kevin J. Anstrom,Adrian F. Hernandez,Alice M. Mascette,Eugene Braunwald +29 more