Pharmacological Inhibition of Hippo Pathway using XMU‐MP‐1 Protects The Heart Against Adverse Effects during Pressure Overload

Background
The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, Mst1 and Mst2, modulate cardiac hypertrophy, apoptosis and fibrosis. Here we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU‐MP‐1 in controlling the adverse effects of pressure overload‐induced hypertrophy.

Methods
We used cultured neonatal rat cardiomyocytes (NRCM) and mouse induced with transverse aortic constriction as in vitro and in vivo models, respectively, to test the effects of XMU‐MP‐1 treatment.

Results
XMU‐MP‐1 treatment significantly increased the activity of the Hippo pathway effector YAP and inhibited phenylephrine‐induced cardiomyocyte hypertrophy in NRCM. XMU‐MP‐1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. 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‐MP‐1 every alternate day for 10 days started from 3 weeks post‐TAC. We found that XMU‐MP‐1‐treated mice showed significantly better contractility than vehicle‐treated mice. Cardiomyocyte cross sectional size and expression of hypertrophic marker (BNP) were reduced in XMU‐MP‐1‐treated mice. The improvement in heart function might be due to the inhibition of cardiomyocyte apoptosis and reduction in fibrosis as we found less TUNEL positive cardiomyocytes and lower levels of fibrosis in XMU‐MP‐1‐treated mice.

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