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 Willis, Cynthia Lander, Jeffrey Robbins

Research output: Contribution to journalArticle

5 Citations (Scopus)

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

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Cardiac Myosins
Fibrosis
Mitogen-Activated Protein Kinases
Protein Kinases
Peptide Fragments
Cardiac Myocytes
Cardiomegaly
Hypertrophy
Transgenic Mice
MMI-0100
myosin-binding protein C
Heart Diseases
Cell Survival
Anatomy
Cardiovascular Diseases
Myocardial Infarction
Control Groups
Peptides
Mutation
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

MMI-0100 inhibits cardiac fibrosis in a mouse model overexpressing cardiac myosin binding protein C. / Meng, Qinghang; Bhandary, Bidur; Osinska, Hanna; James, Jeanne; Xu, Na; Shay-Winkler, Kritton; Gulick, James; Willis, Monte; Lander, Cynthia; Robbins, Jeffrey.

In: Journal of the American Heart Association, Vol. 6, No. 9, e006590, 01.09.2017.

Research output: Contribution to journalArticle

Meng, Q, Bhandary, B, Osinska, H, James, J, Xu, N, Shay-Winkler, K, Gulick, J, Willis, M, 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, vol. 6, no. 9, e006590. https://doi.org/10.1161/JAHA.117.006590
Meng, Qinghang ; Bhandary, Bidur ; Osinska, Hanna ; James, Jeanne ; Xu, Na ; Shay-Winkler, Kritton ; Gulick, James ; Willis, Monte ; Lander, Cynthia ; Robbins, Jeffrey. / MMI-0100 inhibits cardiac fibrosis in a mouse model overexpressing cardiac myosin binding protein C. In: Journal of the American Heart Association. 2017 ; Vol. 6, No. 9.
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AU - Bhandary, Bidur

AU - Osinska, Hanna

AU - James, Jeanne

AU - Xu, Na

AU - Shay-Winkler, Kritton

AU - Gulick, James

AU - Willis, Monte

AU - Lander, Cynthia

AU - Robbins, Jeffrey

PY - 2017/9/1

Y1 - 2017/9/1

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AB - 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.

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