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 language | English (US) |
|---|---|
| Article number | e006590 |
| Journal | Journal of the American Heart Association |
| Volume | 6 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2017 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - MMI-0100 inhibits cardiac fibrosis in a mouse model overexpressing cardiac myosin binding protein C
AU - Meng, Qinghang
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
N2 - 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.
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.
KW - Fibrosis
KW - Hypertrophy/remodeling
KW - Transgenic mice
KW - Transgenic model
UR - http://www.scopus.com/inward/record.url?scp=85029737688&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029737688&partnerID=8YFLogxK
U2 - 10.1161/JAHA.117.006590
DO - 10.1161/JAHA.117.006590
M3 - Article
C2 - 28871043
AN - SCOPUS:85029737688
VL - 6
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 9
M1 - e006590
ER -