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-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. © 2017 the authors.