Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU-MP-1, protects the heart against adverse effects during pressure overload.
Animals
Apoptosis
/ drug effects
Cell Survival
/ drug effects
Cells, Cultured
Hippo Signaling Pathway
Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
/ drug effects
Pressure
Protein Kinase Inhibitors
/ chemistry
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Sulfonamides
/ chemistry
Benzenesulfonamides
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
24
01
2019
revised:
13
05
2019
accepted:
05
07
2019
pubmed:
23
7
2019
medline:
23
9
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
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. 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. 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 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.
Sections du résumé
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
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.
Identifiants
pubmed: 31328787
doi: 10.1111/bph.14795
pmc: PMC6811740
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Sulfonamides
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3956-3971Subventions
Organisme : Medical Research Council
ID : MR/P015816/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/16/77/32400
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/17/78/33304
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/18/40/33767
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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