Abstract 3858: Inhibition of Mammalian Sterile 20-like Kinase 1 Rescues Beta1-Adrenergic Receptor Overexpression: Induced Cardiomyopathy
Chronic beta-adrenergic receptor (beta-AR) stimulation is deleterious and is involved in the pathogenesis of heart failure (HF). Mice with cardiac-specific beta1-AR overexpression exhibit chronically enhanced beta-AR signaling and develop cardiomyopathy as they age (8 –15 mon). Compared with older wild type (WT), the cardiomyopathy in beta1-AR transgenic (Tg) mice is reflected by reduced LV ejection fraction (EF) (53±4% vs 63±2%, p<0.05), and enhanced apoptosis, measured by TUNEL, (1.7±0.2 positive cells/mm2 vs 0.6±0.1 positive cells/mm2, p<0.05) and interstitial fibrosis (9.4±2.9% vs 2.0±0.2%, p<0.05). Mammalian sterile 20-like kinase 1 (Mst1) was overexpressed by 15-fold in beta1-AR Tg mice. Cardiac-specific overexpression of Mst1 in mice also results in increased apoptosis and dilated cardiomyopathy, whereas inhibition of endogenous Mst1 with dominant negative Mst1 (DN-Mst1) prevents apoptosis and cardiac dysfunction. Accordingly we hypothesized that inhibition of Mst1 could rescue the cardiomyopathy induced in beta1-AR Tg mice. We mated beta1-AR Tg mice with cardiac-specific overexpression of DN-Mst1 mice. Mst1 activity in beta1-AR Tg × DN-Mst1 bigenic mice was inhibited by 70%, compared to that in beta1-AR Tg mice, as confirmed by Mst1 kinase assay. Mortality in older bigenic mice compared with the beta1-AR Tg mice, was significantly reduced, p<0.05, from 40% (10 of 25) to 11% (7 of 66), assessed with Chi-Square survival analysis and the Log-Rank test. In addition, the bigenic mice (n=6), compared to beta1-AR Tg mice (see above), exhibited rescued LV function, as reflected by preserved LVEF (63±3%), reduced interstitial fibrosis (3.0±1.1%) and decreased apoptosis (1.0±0.2 positive cells/mm2) (all p<0.05 vs beta1-AR Tg mice). These results suggest that upregulation of Mst1 is involved in the development of chronic beta-AR stimulation-induced cardiomyopathy, since inhibition of endogenous Mst1 suppresses apoptosis and development of interstitial fibrosis, and rescues beta1-AR overexpression-induced cardiomyopathy.
This research has received full or partial funding support from the American Heart Association, National Center.