We recently reported that mutation of the cGMP-dependent Protein Kinase G I alpha (PKGIα) N-terminal leucine zipper (LZ) domain (in the PKGIα LZ mutant, or LZM, mouse) accelerates cardiac remodeling and heart failure after left ventricular (LV) pressure overload, and prevents the anti-remodeling effect of sildenafil . We therefore hypothesized that PKGIα attenuates remodeling by regulating cardiac signaling pathways that are dependent on substrate interactions mediated by its LZ domain. As a first step to identifying cardiac proteins downstream of PKGIα, we screened myocardial lysates for PKGIα LZ domain-interacting proteins. Our previous work revealed a requirement for the PKGIα LZ domain for the activation of anti-remodeling myocardial JNK activity after LV pressure overload. MLK3 is a MAPKKK that contains an LZ domain and activates JNK.