PU.1 inhibition does not attenuate cardiac function deterioration or fibrosis in a murine model of myocardial infarction.

Activated cardiac fibroblasts are involved in both reparative wound healing and maladaptive cardiac fibrosis after myocardial infarction (MI). Recent evidence suggests that PU.1 inhibition can enable reprogramming of profibrotic fibroblasts to quiescent fibroblasts, leading to attenuation of pathologic fibrosis in several fibrosis models. The role of PU.1 in acute MI has not been tested. We designed a randomized, blinded study to evaluate whether DB1976, a PU.1 inhibitor, attenuates cardiac function deterioration and fibrosis in a murine model of MI. A total of 44 Ai9 periostin-Cre transgenic mice were subjected to 60 min of coronary occlusion followed by reperfusion. At 7 days after MI, 37 mice were randomly assigned to control (vehicle) or DB1976 treatment and followed for 2 weeks. Left ventricular ejection fraction (EF), assessed by echocardiography, did not differ between the two groups before or after treatment (final EF, 33.3 ± 1.0% in control group and 31.2 ± 1.3% in DB1976 group). Subgroup analysis of female and male mice showed the same results. There were no differences in cardiac scar (trichrome stain) and fibrosis (interstitial/perivascular collagen; picrosirius stain) between groups. Results from the per-protocol dataset (including mice with pre-treatment EF < 35% only) were consistent with the full dataset. In conclusion, this randomized, blinded study demonstrates that DB1976, a PU.1 inhibitor, does not attenuate cardiac functional deterioration or cardiac fibrosis in a mouse model of MI caused by coronary occlusion/reperfusion.