Abstract 171: PDE5A Inhibition Suppresses Maladaptive but Not Physiological Cardiac Hypertrophy
We have recently shown that PDE5A inhibition has potent antihypertrophic activity in models of increased afterload (transverse aortic constriction; TAC). However, mice subjected to TAC and PDE5A inhibition do show modest cardiac hypertrophy but lack cardiac remodeling. In this series of experiments, we tested the hypothesis that PDE5A inhibition allows physiological cardiac hypertrophy to take place. Mice were subjected to TAC or swimming (4 weeks of 90 min of swimming twice daily). Mice were randomized to receive vehicle or sildenafil citrate (100 mg/kg/d). Mice were evaluated at 4 weeks by echocardiogram, PV Loop, and biochemical analysis. Afterload induced hypertrophy (TAC) and physiologic hypertrophy demonstrated an expected increase in cardiac mass (241 ± 9.7 mg (TAC) vs 152.0 ± 19.5 mg(swimming); P<0.05). TAC was associated with a reduction in heart systolic function and worsening diastolic cardiac function whereas physiologic hypertrophy demonstrated improved cardiac function in all parameters. Sildenafil markedly improved LV function and reduced heart size in TAC (136 ± 6.0 mg, P<0.05 compared to TAC) mice but did not alter function or heart size in swimming mice (153.9 ± 21.3 mg). Swimming mice, while exhibiting significant hypertrophy, did not show increased superoxide activity/staining (by DHE fluorescence) or hydrogen peroxide staining (by dcf fluorescence). Swimming mice showed increased NOS activity when compared to TAC mice and reduced baseline PDE5A activity when compared to TAC. In sum, physiologic hypertrophy is a beneficial adaptive hypertrophy while TAC is associated with maladaptive hypertrophy and results in the progression to heart failure. Sildenafil selectively blocks maladaptive hypertrophy without an effect on physiologic hypertrophy by swimming. Interestingly, both TAC-induced and exercise-induced hypertrophy were both associated with an increase in PI3K/AKT signaling. Sildenafil treatment reduced the expression of p-AKT in TAC-associated hypertrophy, but did not alter the expression of p-AKT in exercise-induced hypertrophy. These findings may reflect differences in special localization of AKT and or PDE5/cGMP signaling in the heart.