Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib

Valentina Sala, Simona Gallo, Stefano Gatti, Enzo Medico, Elisa Vigna, Daniela Cantarella, Lara Fontani, Massimo Natale, James Cimino, Mara Morello, Paolo Maria Comoglio, Antonio Ponzetto, Tiziana Crepaldi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)84-97
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume93
DOIs
Publication statusPublished - Apr 1 2016

Keywords

  • Cardiac hypertrophy
  • Erk1,2
  • Heart failure
  • HGFR
  • Mek1 inhibitor
  • Met receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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