Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn324
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Phosphodiesterase 5 Inhibition Blocks Pressure Overload-Induced Cardiac Hypertrophy Independent of the Calcineurin Pathway
The Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD 21205
1 Department of Comparative Medicine and Comparative Pathology Johns Hopkins University School of Medicine, Baltimore, MD
2 Division of Molecular Cardiovascular Biology, Department of Pediatrics Children's Hospital Medical Center, Cincinnati, OH
Corresponding Author: Eiki Takimoto, M.D., Ph.D. Division of Cardiology, Department of Medicine Johns Hopkins University Medical Institutions 720 Rutland Avenue, Ross- Building Room 850 Baltimore, MD 21205 TEL: (410) 955-7153 FAX: (410) 502-2558 Email: etakimo1{at}jhmi.edu
Aims: Cyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to the pathologic cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL.
Methods and Results: Mice lacking the Cn-Aβ subunit (CnAβ–/–) and wild-type (WT) controls were subjected to trans-aortic constriction (TAC)±SIL (200mg/kg/day, P.O.) for 3 weeks. TAC induced elevation of Cn expression and activity in WT was absent in CnAβ–/– hearts, and the latter accordingly developed less cardiac hypertrophy (50% vs 100% increase in heart weight/ tibia length, p<0.03) and chamber dilation. SIL remained effective in CnAβ–/–mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3β in both groups (the first rising more in CnAβ–/– hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnAβ–/– hearts was also suppressed by SIL.
Conclusion: PDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.
Time for primary review: 15 Days
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  T. Reffelmann and R. A. Kloner Phosphodiesterase 5 inhibitors: are they cardioprotective? Cardiovasc Res, July 15, 2009; 83(2): 204 - 212. [Abstract] [Full Text] [PDF]
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