title: Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib.
abstract: Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.
authors.affiliation: Department of Medical Sciences, University of Turin, 10126 Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sala
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gallo
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy; FPO-IRCCS, 10060 Candiolo, TO, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy; FPO-IRCCS, 10060 Candiolo, TO, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.affiliation: FPO-IRCCS, 10060 Candiolo, TO, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cantarella
authors.affiliation: FPO-IRCCS, 10060 Candiolo, TO, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Fontani
authors.affiliation: Politecnico di Torino, 10129 Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Natale
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: James
authors.initials: J
authors.lastname: Cimino
authors.affiliation: Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Morello
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy; FPO-IRCCS, 10060 Candiolo, TO, Italy.
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ponzetto
authors.affiliation: Department of Oncology, University of Turin, 10126 Turin, Italy. Electronic address: tiziana.crepaldi@unito.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Crepaldi
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D019859:Proto-Oncogene Proteins c-met
keywords: Cardiac hypertrophy; Erk1,2; HGFR; Heart failure; Mek1 inhibitor; Met receptor