The Hippo pathway inhibitor XMU-MP-1 improved cardiomyocyte survival in vitro and preserved cardiac contractility while reducing cellular hypertrophy, apoptosis, and fibrosis in mice following pressure overload.
Does pharmacological inhibition of the Hippo pathway with XMU-MP-1 prevent adverse cardiac remodeling in preclinical models of pressure overload?
Pharmacological inhibition of the Hippo pathway with XMU-MP-1 preserves cardiac function and reduces adverse remodeling in preclinical models of 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.
Triastuti et al. (2019) studied Pressure overload-induced cardiac hypertrophy. XMU-MP-1 vs. Vehicle was evaluated on Cardiac contractility, cellular hypertrophy, apoptosis, and fibrosis. The Hippo pathway inhibitor XMU-MP-1 improved cardiomyocyte survival in vitro and preserved cardiac contractility while reducing cellular hypertrophy, apoptosis, and fibrosis in mice following pressure overload.