Abstract 318: Sildenafil Improves Cardiac Function and Inhibits Protein Kinase C-α Translocation in Advanced-established Hypertrophy
Background: Sildenafil (SIL) inhibits cyclic GMP-specific phosphodiesterase 5A (PDE5A), and prevents cardiac hypertrophy and dysfunction in mice subjected to pressure overload. Its ability to suppress clinically relevant advanced hypertrophy/remodeling and/or improve function is unknown.
Methods and Results: Mice were subjected to transverse aortic constriction (TAC) for 3 weeks to establish hypertrophy and depress function (Table⇓), and then treated with SIL (100 mg/kg/day) or placebo for 6-wks of additional TAC. SIL prevented systolic and diastolic dysfunction and chamber dilation confirmed by echocardiography and invasive pressure-volume analysis (Table⇓). It also blocked progression of further hypertrophy. Myocytes isolated from TAC-SIL hearts had increased sarcomere shortening, higher peak Ca2+ transients and improved relaxation compared to those without SIL treatment. We reported that SIL-mediated effects were coupled with protein kinase G (PKG) stimulation, which may suppress Gαq-coupled signaling. A potential target is protein kinase C-α (PKC-α), which when increased and translocated to the membrane disturbs calcium handling in the sarcoplasmic reticulum, and induces myocyte dysfunction. PKC-α expression was greater in TAC than sham hearts, but SIL did not affect this upregulation. PKC-α was localized to the outer membrane and cytosol in normal myocytes (confocal immunohistochemistry), whereas in TAC myocytes, it translocated to the membrane. This translocation was fully blocked by SIL treatment.
Conclusion: Delayed SIL treatment improves cardiac and myocyte dysfunction and progression of hypertrophy. Inhibition of PKC-α translocation may play an important role to this beneficial response.