Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The PKC family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathologic stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes, which modulate a myriad of cell events, including cell death and cell survival. The isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKCepsilon will protect against hyperglycemic cell injury and left ventricular dysfunction, streptozotocin diabetes mellitus was induced in genetically engineered mice with cardiac specific expression of the PKC translocation activator (RACK). The results demonstrate a striking PKCepsilon cardioprotective phenotype in diabetic [[eplison]]RACK ( agonist) mice, characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress and preserved parameters of left ventricular pump function. Hearts of diabetic agonist mice exhibited selective trafficking of PKC to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein and inhibition of cytochrom c release. We conclude, activation of endogenous PKC in the hearts of diabetic agonist mice, promotes the survival phenotype, attenuates markers of oxidative stress and inhibits the negative inotropic properties of chronic hyperglycemia.