Mitigation of Injury from Myocardial Infarction by Pentamidine, an Inhibitor of the Acetyltransferase Tip60.

Abstract

PURPOSE: There is an urgent unmet need for new pharmacologic approaches that promote re-muscularization and repair following myocardial infarction (MI). We previously reported that genetic depletion of the acetyltransferase Tip60 after MI in a mouse model activates the CM cell-cycle, reduces scarring, and restores cardiac function, and that these beneficial effects are mimicked by the Tip60-selective inhibitor TH1834. Here, we investigated whether the FDA-approved anti-microbial agent pentamidine, a Tip60 inhibitor from which TH1834 is derived, also protects from the damaging effects of MI. METHODS: Adult (10-14 weeks old) C57Bl/6 mice were subjected to permanent left coronary artery ligation to induce MI. Subsequently, echocardiography, electrocardiography, cardiac staining, and molecular analyses were performed to monitor the effects of treatment with pentamidine on cardiac injury and function. RESULTS: We report that transient systemic administration of pentamidine on days 3-16 post-MI at a daily dose of 3 mg/kg efficiently improved cardiac function for up to ten months. This was accompanied by improved survival, diminished scarring, and increased activation of cell-cycle markers in CMs located in the infarct border zone in the absence of hypertrophy. Histological assessments suggested that post-MI treatment with pentamidine reduced site-specific acetylation of the minor histone variant H2A.Z at lysines K4 and K7 in CMs, indicative of the dedifferentiation process which must occur prior to CM proliferation. Treating mice with pentamidine post-MI produced no prominent electrophysiological changes. CONCLUSIONS: These findings support the translational potential of pentamidine for treatment of MI, and provide evidence that functional improvement is mediated, in part, by CM renewal due to inhibition of the acetyltransferase activity of Tip60.