Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU-MP-1, protects the heart against adverse effects during pressure overload

  • Br J Pharmacol. 2019 Oct;176(20):3956-3971. doi: 10.1111/bph.14795.
Efta Triastuti  1  2 ,  Ardiansah Bayu Nugroho  1 ,  Min Zi  1 ,  Sukhpal Prehar  1 ,  Yulia Suciati Kohar  1  3 ,  Thuy Anh Bui  1 ,  Nicholas Stafford  1 ,  Elizabeth J Cartwright  1 ,  Sabu Abraham  1 ,  Delvac Oceandy  1
Affiliations
  • 1. Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • 2. Department of Pharmacy, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • 3. Department of Biochemistry, Faculty of Medicine, YARSI University, Jakarta, Indonesia.
PMID: 31328787 DOI: 10.1111/bph.14795
Abstract

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.

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