Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NF-kappaB is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NF-kappaB nuclear translocation and transcriptional activity, accompanied by IkappaB-alpha phosphorylation and degradation. Consistently, myotrophin-induced NF-kappaB activation was enhanced by wild-type IkappaB kinase (IKK) beta and abolished by the dominant-negative IKKbeta or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc) and also enhanced protein synthesis were partially inhibited by a potent NF-kappaB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominant-negative form of IkappaB-alpha or IKKbeta also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC-IKK-NF-kappaB pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.