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PRE-CLINICAL RESEARCH

Sildenafil Stops Progressive Chamber, Cellular, and Molecular Remodeling and Improves Calcium Handling and Function in Hearts With Pre-Existing Advanced Hypertrophy Caused by Pressure Overload

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^_*,_*

^_* Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
Department of Comparative Medicine and Comparative Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Manuscript received March 18, 2008; revised manuscript received July 2, 2008, accepted August 11, 2008.

^_* 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 (Email: dkass{at}jhmi.edu).

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- (PKC) can both lower phosphorylated phospholamban and depress myocyte calcium cycling. The Cn expression and PKC activation (outer membrane translocation) were enhanced by chronic TAC and reduced by SIL treatment. Expression of PKC and PKC 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 PKC activation may be important to this improvement.

Key Words: PDE5 • pressure overload • hypertrophy • myocyte • cardiac function

Abbreviations and Acronyms   cGMP = cyclic guanosine monophosphate   Cn = calcineurin   ISO = isoproterenol   LV = left ventricular   NOS = nitric oxide synthase   PDE5A = phosphodiesterase 5A   PKC = protein kinase C-   PKG = protein kinase G   SERCA 2a = sarcoplasmic reticulum Ca2+ adenosine triphosphatase   SIL = sildenafil   SR = sarcoplasmic reticulum   TAC = transverse aortic constriction

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