Abstract 15839: Myocardial Phosphodiesterase 5 is Increased in Patients With Severe Aortic Stenosis and Contributes to Left Ventricular Dysfunction in Pressure-Overloaded Mice
Background - Phosphodiesterase 5 (PDE5) modulates cyclic guanosine monophosphate (cGMP) levels in heart disease, but its role in pressure overload (PO)-induced cardiac remodeling remains incompletely understood.
Methods and Results - PDE5 expression was higher in LV tissue of aortic stenosis patients (AS; n=18) compared to controls (n=6) as evidenced by qPCR (normalized mRNA levels: 0.0103 ± 0.0038 in AS vs 0.0003 ± 0.0002 in controls, P<0.05) and immunoblot analysis. PDE5 expression was prominent in microvascular endothelium and scattered cardiomyocytes. In mice with severe transverse aortic constriction (TAC)-induced hypertrophy, PDE5 expression was increased, and predominantly localized in cardiomyocytes. To investigate the role of increased PDE5 during cardiac stress, we compared LV remodeling after TAC in mice with cardiomyocyte-specific PDE5 overexpression (50 PDE5-TG) and in wild-type mice (37 WT). After 10w TAC, functional remodeling was more impaired in PDE5-TG (Table 1), while indices of cardiac hypertrophy (fractional heart weight, cardiomycoyte width), fibrosis (sirius red, qPCR), apoptosis (TUNEL, qPCR) and oxidative stress (immunoblot) were similar as in WT. In WT, myocardial cGMP levels increased proportionately with HW/BW, but not in PDE5-TG (P<0.05). Moreover, PDE5-TG displayed lower SERCA2 levels, shown by qPCR (normalized mRNA levels: 1.01 ± 0.10 in PDE5-TG vs 1.44 ± 0.17 in WT, P<0.05) and immunoblot analysis. Finally, passive force in skinned cardiomyocytes measured at 2.3 micrometer was greater in PDE5-TG (3.0 ± 0.5 kN/m2) than in WT (1.7 ± 0.2 kN/m2, P<0.05), and responsive to PKGIα administration.
Conclusions - Myocardial PDE5 expression is increased in AS and in mice with a severe response to chronic PO. Cardiomyocyte-specific PDE5 overexpression is associated with lower myocardial SERCA2 levels, increased passive force, and impaired LV function in PO-mice. PDE5 is an attractive therapeutic target in hypertrophic remodeling.
- © 2011 by American Heart Association, Inc.