Background:
Hypertrophic cardiomyopathy is considered one of the most common genetic heart disorders, occurring with a frequency of about 1 in 200, with approximately 30% of those affected showing mutations within the cardiac myosin-binding protein C (cMyBP-C) gene (
MYBPC3
). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40kDa fragment in mouse cardiomyocytes (MyBP-C
40k
) leads to hypertrophic cardiomyopathy), fibrosis and heart failure. Fibrosis can occur in many cardiovascular diseases and the p38-MK2 signaling pathway has been implicated in a variety of fibrotic processes. Recent studies demonstrated that MK2 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:
Non-transgenic and MyBP-C
40k
transgenic (Dtg) 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 Dtg group, MMI-0100 treatment reduced cardiac fibrosis, decreased cardiac hypertrophy and prolonged survival.
Conclusions:
Pharmaceutical inhibition of p38-MK2 signaling via MMI-0100 treatment is beneficial in the context of fibrotic MyBPC
40k
disease.