Abstract 82: Reduction of SHP2’s Phosphatase Activity Improves Cardiac Adaptation to Pressure and Volume Overload

Since the inability of the heart to adapt to pathological stress results in heart failure, supporting cardiac stress adaptation may improve clinical outcome. We hypothesized that the protein tyrosine phosphatase SHP2 controls adaptation by modulating several signaling pathways involved. To test whether SHP2 plays an active role in stress adaptation, we generated transgenic (TG) mice with cardiomyocyte-specific overexpression of Q510E-SHP2, which is a dominant-negative mutant (dnSHP2). Under unstressed conditions, TG mice do not exhibit a cardiac phenotype. TG and nonTG (NTG) mice were subjected to pressure overload by transverse aortic constriction (TAC) or to volume overload by inducing large myocardial infarction (MI) via coronary artery ligation. Expression of dnSHP2 significantly improved stress adaptation after TAC (n=17 TG, n=13 NTG). Twelve weeks after banding, TG mice exhibited well preserved contractile function with significantly higher fractional shortening (FS) [TG 33.2±1.7 vs. NTG 22.2±1.5 %, p<0.001] and ejection fraction (EF) [TG 67.7±2.7 vs. NTG 50.3±3.0 %, p<0.001]. dnSHP2 TGs also had smaller left ventricular (LV) chamber dimensions [LV inner diameter at end-diastole (LVIDd) TG 4.4±0.2 vs. NTG 5.1±0.2 mm, p=0.02]. There were no significant differences in ventricular wall thickness or heart weights, indicating that the degree of hypertrophy in response to TAC was not affected by dnSHP2 expression. In response to volume overload induced by large MI (n=22 TG, n=24 NTG), TG hearts displayed only a trend towards improved contractile function [FS TG 21.3±1.5 vs. NTG 18.9±1.1%, EF TG 48.4±2.7 vs. NTG 44.2±2.1%]. However, chamber dimensions were better preserved in TGs [LVIDd TG 5.1±0.1 vs. NTG 5.7±0.2 mm, p=0.03]. In summary, dnSHP2 expression ameliorated LV chamber dilation and increased contractile function under pressure overload. In TGs subjected to volume overload, reduced LV dimensions were observed but with only a trend towards improved contractile function. Taken together, it is evident that reducing SHP2’s phosphatase activity indeed improves cardiac stress adapation, making SHP2 a potential novel therapeutic target.

Duke Scholars

Author Rajika Roy Surgery, Cardiovascular and Thoracic Surgery