Abstract 3733: Inhibiting Phosphorylation of SMAD2 Preserves Cardiac Function During Pressure Overload
The TGF-beta superfamily has been postulated to play a role in regulating myocardial remodeling. SMAD2 mediates intracellular signaling by TGF-beta family members, and phosphorylation of SMAD2 might induce both deleterious and cardioprotective effects. We hypothesized that inhibiting phosphorylation of SMAD2 in pressure overload preserves left ventricular (LV) function by reducing myocardial fibrosis and cardiomyocyte remodeling. C57BL/6 mice were randomized to one of the following four groups: one week of banding of the ascending aorta (AB) or sham procedure and receiving chow without (STD) or with an inhibitor of SMAD2 phosphorylation (SM16). SM16 treatment improved fractional shortening (FS) (31.8±2.6 % AB SM16 vs. 23.6±2.0 % AB STD, n=11–12, p=0.02) and mitral deceleration slope (Mdec) (25.6±2.2 m/s2 AB SM16 vs. 35.5±2.4 m/s2 AB STD, n=11–12, p<0.01), indicating improvement of both systolic and diastolic function. This was further supported by a negative correlation between p-SMAD2 and systolic and diastolic peak tissue velocity (R=0.47, p=0.04 and R=0.56, p=0.01, respectively, n=19). AB induced 37 % increased LV weight in both AB groups (n=32–40) and LV end diastolic diameter was equal in the four groups (n=6–12). However, markers of cardiomyocyte remodeling were reduced by SM16 as demonstrated by RT-PCR (n=5–8); the increased expression of alpha skeletal actin (7.3-fold up-regulation in AB) and myosin heavy chain beta (5.5-fold) was significantly lower in mice receiving SM16. The reduction in expression of SERCA2 in AB mice (1.8-fold down-regulation) was inhibited in the SM16 group. Moreover, the increased expression of collagen genes was dramatically reduced by SM16. There was, however, no difference in LV collagen protein between the four groups (n=10), as demonstrated by HPLC of hydroxyproline. This indicates beneficial cardiac effects of SM16 beyond inhibition of fibrosis. We conclude that inhibiting phosphorylation of SMAD2 preserves cardiac function in LV pressure overload. The improved systolic and diastolic function, as measured by improved FS and Mdec, might be explained by mechanisms beyond inhibition of myocardial fibrosis, possibly by effects on contractile proteins and Ca++ handling in the cardiomyocytes.