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Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function
Takahiro Nagayama1, Steven Hsu, Manling Zhang
1Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Insights
Sildenafil (SIL) treatment halts cardiac remodeling and dysfunction in advanced heart disease by improving calcium handling. This PDE5A inhibitor reduces calcineurin and PKCalpha activity, offering a potential therapeutic strategy for established cardiac conditions.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- Cardiac hypertrophy and dysfunction are significant health concerns.
- Sildenafil (SIL) is known to inhibit phosphodiesterase type 5A (PDE5A) and prevent early cardiac remodeling in mice.
- Its efficacy in treating established, advanced cardiac disease remains unclear.
Purpose of the Study:
- To evaluate the effectiveness of PDE5A inhibition with sildenafil in established pressure-overload-induced cardiac hypertrophy and remodeling.
- To investigate the underlying cellular and molecular mechanisms responsible for sildenafil's therapeutic effects.
Main Methods:
- Mice underwent transverse aortic constriction (TAC) for 3 weeks to induce cardiac hypertrophy and dilation.
- Subsequent treatment involved 6 weeks of additional TAC with either sildenafil (100 mg/kg/day) or placebo.
- Cellular and molecular analyses were performed to assess cardiac function, remodeling, and signaling pathways.
Main Results:
- Sildenafil treatment arrested progressive chamber dilation, dysfunction, fibrosis, and molecular remodeling in established cardiac disease.
- It increased myocardial protein kinase G activity and improved isolated myocyte contractility and relaxation.
- SIL restored SERCA2a and phospholamban (PLB) expression and increased PLB phosphorylation, indicating enhanced calcium handling. It also reduced calcineurin and PKCalpha activation.
Conclusions:
- Sildenafil treatment can prevent further cardiac and myocyte dysfunction and remodeling in well-established hypertrophic cardiac disease.
- The therapeutic benefits are associated with improved calcium cycling.
- Reduced calcineurin and PKCalpha activation may be key mechanisms mediating these improvements.
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 Ca(2+) transients and decay compared with nontreated TAC hearts. The SIL treatment restored gene and protein expression of sarcoplasmic reticulum Ca(2+) 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-alpha (PKCalpha) can both lower phosphorylated phospholamban and depress myocyte calcium cycling. The Cn expression and PKCalpha activation (outer membrane translocation) were enhanced by chronic TAC and reduced by SIL treatment. Expression of PKCdelta and PKCepsilon 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 PKCalpha activation may be important to this improvement.
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