MMI-0100 inhibits cardiac fibrosis in a mouse model overexpressing cardiac myosin binding protein C

Qinghang Meng, Bidur Bhandary, Hanna Osinska, Jeanne James, Na Xu, Kritton Shay-Winkler, James Gulick, Monte S. Willis, Cynthia Lander, Jeffrey Robbins

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background--Cardiac stress can trigger production of a 40-kDa peptide fragment derived from the amino terminus of the cardiac myosin-binding protein C. Cardiac stress, as well as cMyBP-C mutations, can trigger production of 1 such truncated protein fragment, a 40-kDa peptide fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40-kDa fragment in mouse cardiomyocytes (cMyBP-C40k) leads to cardiac disease, fibrosis, and death within the first year. Fibrosis can occur in many cardiovascular diseases, and mitogen-activated protein kinase--activated protein kinase-2 signaling has been implicated in a variety of fibrotic processes. Recent studies demonstrated that mitogen-activated protein kinase--activated protein kinase-2 inhibition using the cell-permeant peptide inhibitor MMI-0100 is protective in the setting of acute myocardial infarction. We hypothesized that MMI-0100 might also be protective in a chronic model of fibrosis, produced as a result of cMyBP-C40k cardiomyocyte expression. Methods and Results--Nontransgenic and cMyBP-C40k inducible transgenic mice were given MMI-0100 or PBS daily for 30 weeks. In control groups, long-term MMI-0100 was benign, with no measurable effects on cardiac anatomy, function, cell viability, hypertrophy, or probability of survival. In the inducible transgenic group, MMI-0100 treatment reduced cardiac fibrosis, decreased cardiac hypertrophy, and prolonged survival. Conclusions--Pharmaceutical inhibition of mitogen-activated protein kinase--activated protein kinase-2 signaling via MMI-0100 treatment is beneficial in the context of fibrotic cMyBPC40k disease.

Original languageEnglish (US)
Article numbere006590
JournalJournal of the American Heart Association
Volume6
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

Keywords

  • Fibrosis
  • Hypertrophy/remodeling
  • Transgenic mice
  • Transgenic model

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Meng, Q., Bhandary, B., Osinska, H., James, J., Xu, N., Shay-Winkler, K., Gulick, J., Willis, M. S., Lander, C., & Robbins, J. (2017). MMI-0100 inhibits cardiac fibrosis in a mouse model overexpressing cardiac myosin binding protein C. Journal of the American Heart Association, 6(9), [e006590]. https://doi.org/10.1161/JAHA.117.006590