Author + information
- Received March 18, 2008
- Revision received July 2, 2008
- Accepted August 11, 2008
- Published online January 13, 2009.
- Takahiro Nagayama, PhD⁎,
- Steven Hsu, BA⁎,
- Manling Zhang, MD, PhD⁎,
- Norimichi Koitabashi, MD, PhD⁎,
- Djahida Bedja, MS†,
- Kathleen L. Gabrielson, PhD†,
- Eiki Takimoto, MD, PhD⁎ and
- David A. Kass, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. David A. Kass, Division of Cardiology, Johns Hopkins Medical Institutions, Ross Research Building, Room 858, 720 Rutland Avenue, Baltimore, Maryland 21205
Objective This study sought to test the efficacy of phosphodiesterase type 5A (PDE5A) inhibition for treating advanced hypertrophy/remodeling caused by pressure overload, and to elucidate cellular and molecular mechanisms for this response.
Background Sildenafil (SIL) inhibits cyclic guanosine monophosphate–specific PDE5A and can blunt the evolution of cardiac hypertrophy and dysfunction in mice subjected to pressure overload. Whether and how it ameliorates more established advanced disease and dysfunction is unknown.
Methods Mice were subjected to transverse aortic constriction (TAC) for 3 weeks to establish hypertrophy/dilation, and subsequently treated with SIL (100 mg/kg/day) or placebo for 6 weeks of additional TAC.
Results The SIL arrested further progressive chamber dilation, dysfunction, fibrosis, and molecular remodeling, increasing myocardial protein kinase G activity. Isolated myocytes from TAC-SIL hearts showed greater sarcomere shortening and relaxation, and enhanced Ca2+ transients and decay compared with nontreated TAC hearts. The SIL treatment restored gene and protein expression of sarcoplasmic reticulum Ca2+ uptake adenosine triphosphatase (SERCA2a), phospholamban (PLB), and increased PLB phosphorylation (S16), consistent with improved calcium handling. The phosphatase calcineurin (Cn) and/or protein kinase C-α (PKCα) can both lower phosphorylated phospholamban and depress myocyte calcium cycling. The Cn expression and PKCα activation (outer membrane translocation) were enhanced by chronic TAC and reduced by SIL treatment. Expression of PKCδ and PKCε also increased with TAC but were unaltered by SIL treatment.
Conclusions SIL treatment applied to well-established hypertrophic cardiac disease can prevent further cardiac and myocyte dysfunction and progressive remodeling. This is associated with improved calcium cycling, and reduction of Cn and PKCα activation may be important to this improvement.
This study was supported by National Institute of Health Grants HL-59408, HL-07227, and HL-084946, an Abraham and Virginia Weiss Professorship, the Peter Belfer Laboratory, and the Robert Kubicki Research Fund (to Dr. Kass); a fellowship grant from Daiichi-Sankyo Inc. (to Dr. Nagayama); T32-HL-07227 (to Dr. Zhang); an American Heart Association Scientist Development Grant Award and HL-084946 (to Dr. Takimoto); and a fellowship grant from the Japan Heart Foundation (to Dr. Koitabashi).
- Received March 18, 2008.
- Revision received July 2, 2008.
- Accepted August 11, 2008.
- American College of Cardiology Foundation