Abstract
Background and PurposeThe 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 ApproachWe 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 ResultsXMU‐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 ImplicationsThe Hippo pathway inhibitor, XMU‐MP‐1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload.
Highlights
Heart failure has become a global health problem with projections of increasing prevalence and rising economic burden in the decade (Cook, Cole, Asaria, Jabbour, & Francis, 2014; Mozaffarian et al, 2015)
The expression and activation of core components of the Hippo pathway such as yes‐associated protein (YAP), large tumour suppressor kinase (Lats), and Salv were significantly elevated in patients with heart failure (Leach et al, 2017) and we have previously shown expression of mammalian Ste‐20 like kinase 2 (Mst2) was increased in a mouse model of pressure overload hypertrophy (Zi et al, 2014)
The key finding of this study is that treatment with the mammalian Ste‐20 like kinase 1 (Mst1)/2 inhibitor XMU‐MP‐1 improved cardiac function and reduced apoptosis and fibrosis in a mouse model of cardiac hypertrophy due to pressure overload
Summary
Heart failure has become a global health problem with projections of increasing prevalence and rising economic burden in the decade (Cook, Cole, Asaria, Jabbour, & Francis, 2014; Mozaffarian et al, 2015). The expression and activation of core components of the Hippo pathway such as YAP, Lats, and Salv were significantly elevated in patients with heart failure (Leach et al, 2017) and we have previously shown expression of Mst was increased in a mouse model of pressure overload hypertrophy (Zi et al, 2014). These results indicate that in the heart, Hippo pathway components can be triggered following pathological stimuli, and targeting the Hippo pathway may have clinical relevance. In this study, we used both in vitro and in vivo models to investigate the effects of the Mst1/2 inhibitor XMU‐MP‐1 on pathological cardiac hypertrophy
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