Abstract 18817: The Role of Mst1 and Mst2 in Pressure Overload-Induced Hypertrophy and Failure
Mammalian sterile 20-like kinases 1 and 2 (Mst1/2) are highly conserved and are thought to have similar pro-apoptotic and anti-cell growth properties. Previous work has demonstrated that increased expression of Mst1 causes robust cardiomyocyte apoptosis, heart failure and premature death in mice, yet the function of endogenous Mst1/2 has not been investigated. The goal of this study was to determine the role of Mst1 and Mst2 in the development of heart failure using genetically altered Mst isoform-specific mice. Systemic deletion of both Mst isoforms is embryonic lethal; therefore we utilized mice harboring floxed Mst1 alleles on an Mst2-/- background and bred them with α-MHC Cre mice to disrupt both isoforms in cardiomyocytes (Mst DKO). Animals were subjected to transverse aortic constriction for 4 weeks or sham. Echocardiography was performed prior to intervention and immediately before sacrifice. At 8 weeks of age, no significant differences in the cardiac phenotype were observed between control, Mst1-/-, Mst2-/- or Mst DKO mice. In response to pressure overload (PO), control mice had increased heart weight/tibia length (HW/TL), left ventricle weight/tibia length (LVW/TL) and cardiomyocyte cross-sectional area as expected. Surprisingly, this hypertrophic response was significantly attenuated in Mst1-/- and Mst2-/- mice. Interestingly, Mst DKO mice hypertrophied similar to controls. Apoptosis and fibrosis were increased, and LV ejection fraction (LVEF) was decreased after PO in control mice. Mst1-/- and Mst2-/- mice had attenuated apoptosis and fibrosis; however, LVEF was decreased to levels similar to controls. Interestingly, Mst DKO mice also showed attenuated apoptosis and fibrosis but had significantly worse LVEF compared to control mice. Studies are ongoing to address the mechanism responsible for worsened cardiac function observed in Mst DKO mice despite suppression of fibrosis and apoptosis after PO.
- © 2013 by American Heart Association, Inc.