MMI-0100 Inhibits Cardiac Fibrosis in a Mouse Model Overexpressing Cardiac Myosin Binding Protein C.

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.

• Authors: Qinghang Meng, Bidur Bhandary, Hanna Osinska, Jeanne James, Na Xu, Kritton Shay-Winkler, James Gulick, Monte S Willis, Cynthia Lander, Jeffrey Robbins
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 6 Issue 9 (Sep 04 2017) ISSN: 2047-9980 [Electronic] England
• PMID: 28871043 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Chemical References

• Acta2 protein, mouse
• Actins
• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• MMI-0100
• Peptides
• Protein Kinase Inhibitors
• myosin-binding protein C
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases

Topics

• Actins (metabolism)
• Animals
• Cardiomyopathies (enzymology, genetics, physiopathology, prevention & control)
• Carrier Proteins (genetics, metabolism)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Fibroblasts (drug effects, enzymology, pathology)
• Fibrosis
• Hypertrophy, Left Ventricular (genetics, physiopathology, prevention & control)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Peptides (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Up-Regulation
• Ventricular Remodeling (drug effects)