RAPGEF3 and ischemia reperfusion injury: The demonstration that EPAC1 inhibition prevents Dox-induced MPTP opening and cardiomyocyte death suggests that EPAC1 may play a similar deleterious role in Dox-associated cardiotoxicity and ischemia/reperfusion injury and that MPTP is a major downstream effector in the cardiac cell death signaling cascade regulated by EPAC1.