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

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 ‐C 40k ) 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 ‐C 40k cardiomyocyte expression. Methods and Results Nontransgenic and cMyBP ‐C 40k 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 cMyBPC 40k disease.