ZF143 Enhances Zebrafish Heart Regeneration and Improves Mouse Heart Function After an LAD Injury

Abstract

Heart disease is the leading cause of morbidity and mortality in the Western world due to a limited regenerative capacity. In lieu of new muscle synthesis in response to injury, the human heart replaces necrotic tissue with deposition of a non‐contractile scar. While a scar provides short‐term benefits, its long‐term perdurance often culminates in heart failure. Thus, there is a tremendous unmet need for therapeutic intervention that stimulates cardiomyocyte proliferation. The adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte creation and complete recovery of lost heart function when challenged with an acute injury. In this study, we employed the zebrafish to screen a limited number of compounds in order to identify molecules that may amplify genetic networks that underscore regenerative capacity. We identified ZF143, a naturally occurring compound that greatly enhances regeneration of heart tissues. ZF143 increases cardiomyocyte proliferation indices by over 200% when compared with control animals. This enhancement in proliferation is accompanied with new muscle creation and decreases in scar tissue deposition within the wounded apex. Importantly, ZF143 is able to restore regenerative capacity in a zebrafish genetic model with repressed heart regenerative capacity. Additionally, in blinded adult mice studies, ZF143 profoundly increased survival under conditions of LAD injury. This increased survival is accompanied with improved heart function and decreased infarct size following a 1‐month treatment with ZF143. Collectively, this data suggests ZF143 could have strong therapeutic applications for stimulating heart muscle regeneration.