Pharmacological Inhibition of Hippo Pathway, with the Novel Kinase Inhibitor XMU‐MP‐1, Protects the Heart Against Adverse Effects During Pressure Overload

BACKGROUND AND PURPOSE:The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste-20 like kinase 1 (Mst1) and mammalian Ste-20 like kinase 2 (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. EXPERIMENTAL APPROACH:We used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU-MP-1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT-PCR and immunohistochemical methods in vivo. KEY RESULTS:XMU-MP-1 treatment significantly increased activity of the Hippo pathway effector yes-associated protein and inhibited phenylephrine-induced hypertrophy in NRCM. XMU-MP-1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU-MP-1 (1 mg·kg-1 ) every alternate day for 10 further days. XMU-MP-1-treated mice showed better cardiac contractility than vehicle-treated mice. Cardiomyocyte cross-sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU-MP-1-treated mice. Improved heart function in XMU-MP-1-treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis. CONCLUSIONS AND IMPLICATIONS:The Hippo pathway inhibitor, XMU-MP-1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload.