102 Pharmacological modulation of the hippo pathway protects against adverse cardiac remodelling

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Abstract

The Hippo pathway has emerged as a potential therapeutic target to control adverse cardiac remodelling as it is an important regulator of cell growth, regeneration and apoptosis. We and others have demonstrated that genetic knockout of Mst2 and Mst1, the core components of this pathway, results in protection against pressure overload hypertrophy in mice. Here we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU-MP1 in controlling cardiomyocyte hypertrophy, survival and apoptosis.

XMU-MP-1 treatment significantly increased the activity of the Hippo pathway effector YAP in cultured cardiomyocytes as indicated by YAP-luciferase assay and analysis of YAP sub-cellular localization. Additionally, XMU-MP-1 increased cardiomyocyte survival and reduced apoptosis in response to oxidative stress (treatment with H2O2) as shown by MTT and TUNEL assays. We also found that XMU-MP-1 significantly inhibited phenylephrine-induced cardiomyocyte hypertrophy as indicated by cell size measurement and BNP expression. The pro-hypertrophic ERK1/2 pathway might be involved in the process since we found reduced phosphorylation of ERK1/2 following XMU-MP-1 treatment. To investigate the effects of XMU-MP-1 in vivo we subjected C57Bl/6 mice to transverse aortic constriction (TAC) and treated these mice with 1 mg/kg BW XMU-MP1 every alternate day for 10 days. Mice treated with XMU-MP1 showed significantly better contractility than vehicle-treated mice (ejection fraction) although no difference in hypertrophy was observed.

In summary, Hippo pathway inhibitor XMU-MP-1 reduces cellular hypertrophy and improves survival in cultured cardiomyocytes whilst preserving cardiac function in vivo following pressure overload.

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