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

• Published in: Journal of the American College of Cardiology Vol. 53; no. 2; pp. 207 - 215
• Main Authors: Nagayama, Takahiro, PhD, Hsu, Steven, BA, Zhang, Manling, MD, PhD, Koitabashi, Norimichi, MD, PhD, Bedja, Djahida, MS, Gabrielson, Kathleen L., PhD, Takimoto, Eiki, MD, PhD, Kass, David A., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 13.01.2009; Elsevier; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Calcineurin - metabolism; Calcium; Calcium - metabolism; cardiac function; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Catheters; Gene expression; Gene Expression - drug effects; Heart - drug effects; Heart failure; Histology; hypertrophy; Hypertrophy, Left Ventricular - physiopathology; Internal Medicine; Kinases; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mortality; myocyte; Nitric oxide; PDE5; Phosphodiesterase Inhibitors - pharmacology; Phosphorylation; Piperazines - pharmacology; Pressure - adverse effects; pressure overload; Protein expression; Protein Kinase C-alpha - metabolism; Proteins; Purines - pharmacology; Rodents; Sildenafil Citrate; Studies; Sulfones - pharmacology; Ventricular Dysfunction, Left - metabolism; Ventricular Remodeling - drug effects; United States > US; California; cyclic guanosine monophosphate; hypertrophy; cGMP; LV; Cn; isoproterenol; calcineurin; pressure overload; protein kinase C-α; sarcoplasmic reticulum; cardiac function; protein kinase G; left ventricular; nitric oxide synthase; SR; PDE5; ISO; myocyte; phosphodiesterase 5A; PKCα; PKG; sildenafil; NOS; SIL; TAC; transverse aortic constriction; PDE5A; SERCA 2a; sarcoplasmic reticulum Ca 2+ adenosine triphosphatase; Heart; Progressive; Vascular remodeling; Calcium; Overload; Advanced stage; Circulatory system; Sildenafil; Cardiology; Cell; Pressure; Hypertrophy
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2008.08.069

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.