Abstract 513: FGF1 Stimulation/ p38 Inhibition Induces Cardiomyocyte Mitosis, Reduces Scarring and Improves Function after Myocardial Infarction
Zebrafish hearts regenerate through cardiomyocyte proliferation. When cardiomyocyte proliferation is blocked, injured zebrafish hearts scar. Mammalian cardiomyocytes have limited proliferation potential, and injured mammalian hearts scar. Here we show in a blinded and randomized study in 118 rats that inducing cardiomyocyte mitosis following acute myocardial infarction is associated with markedly reduced scarring and improved cardiac function. FGF1 and p38 inhibitor treatment of rats following acute myocardial injury induced a 3.4 ± 0.4-fold (n ≥ 9, p < 0.01) increase of cardiomyocyte mitosis as determined by histone H3 phosphorylation. All increased mitotic activity was localized to the injury site, both within the injured tissue and at the border. At three months following injury, four weeks of FGF1 and p38 inhibitor therapy reduced cardiac scarring by 52.3 ± 12.1% (n ≥ 7, p < 0.01). Cardiac thinning was reduced by 54.6 ± 14.4% (n ≥ 7, p < 0.01). FGF1 therapy by itself increased the density of blood vessels within injured tissue by 56.7 ± 15.6% (n ≥ 7, p < 0.01), whereas p38 inhibition by itself had no effect on angiogenesis. Cardiac function was dramatically enhanced by FGF1 and p38 inhibitor therapy as measured by echocardiogaphy. Cardiac function was markedly improved and there was no significant difference in cardiac function between sham and treated animals. In conclusion, these data indicate that FGF1/p38 inhibitor treatment induces cardiomyocyte mitosis and rescues cardiac structure and function following injury, providing a promising new therapeutic approach in the setting of myocardial damage.