Abstract 12695: B-type Natriuretic Peptide Promoter-mediated Suppression of Protein Phosphatase 1β Mitigates Pressure Overload-induced Heart Failure in Mice
Aberrant increase in protein phosphatase 1(PP1) activity has been shown to be associated with inefficient sarcoplasmic reticulum Ca2+ cycling in failing hearts, leading to poor prognosis in chronic heart failure. We previously reported that adeno-associated virus 9 (AAV9)-medicated heart failure-inducible short hairpin RNA (shRNA) of protein phosphatase 1β prevented left ventricular (LV) remodeling in genetic mice cardiomyopathy. However, it is still controversial whether such PP1 inhibition strategy is clinically relevant as treatment of heart failure. In the present study, we hypothesized that heart failure-inducible suppression of PP1β ameliorates progression of pressure overload-induced heart failure in mice, a clinically relevant model.
Methods: AAV9 vector encoding PP1βshRNA or negative control (NC) shRNA driven by B-type natriuretic peptide (BNP) promoter was employed to test the hypothesis. AAV9-BNP-EmGFP-PP1βshRNA and AAV9-BNP-EmGFP-NCshRNA were introduced into in vivo hearts via tail vein injection (4×1011 GC/mice) in 10-week-old C57B6 mice. Two weeks after AAV9 injection, transverse aortic banding (TAB) was operated and cardiac function was assessed every 2 weeks by echocardiography, followed by LV catheterization at 1 month.
Results: TAB operation induced a progressive chamber dilation with marked decrease in LV systolic function (% fractional shortening: %FS) for 1 month. PP1βshRNA treatment prevented such LV remodeling and ameliorated systolic dysfunction (%FS: 21±1% in PP1βshRNA group vs. 15±1% in NCshRNA group, p<0.01) . Myocardial PP1β expression was significantly suppressed by 15% in PP1βshRNA group (p<0.001). The ratios of heart weight / body weight (HW/BW) and lung weight / body weight (LW/BW) were significantly smaller in the PP1βshRNA group compared with those of the NCshRNA group (HW/BW: 9.20±0.49 vs. 10.6±0.45 mg/g; p<0.05, LW/BW: 9.27±0.99 vs. 13.3±1.29 mg/g; p<0.05, respectively). Moreover, PP1βshRNA treatment showed a significant decrease in LV end-diastolic pressure (28.8±1.20 to 17.2±3.93 mmHg, p<0.05) and 40% reduction in BNP mRNA compared with NCshRNA group.
Conclusion: Heart failure-inducible suppression of PP1β proposes a promising therapeutic strategy for heart failure.
- © 2012 by American Heart Association, Inc.