Expressional reprogramming of survival pathways in rat cardiocytes by neuregulin-1beta.

Neuregulin/ErbB2-induced kinase signaling provides essential survival and protection clues for functional integrity of the adult heart and skeletal muscle. To define the regulatory pathways involved in neuregulin-dependent muscle cell survival, we set out to map the largely unknown transcript targets of this growth/differentiation factor in cardiocytes. Freshly isolated adult primary rat cardiocytes were treated for 24 h with recombinant human neuregulin-1beta (NRG-1beta, 30 ng/ml). Transcript level alterations in NRG-1beta-treated and control cardiocytes (n = 6) were identified with Atlas Rat Toxicology 1.2 cDNA arrays (BD Clontech) and established permutation L1 regression analysis. Selected transcriptional adjustments were confirmed by RT-PCR and Western blotting. Involvement of MAPK pathways was verified with the inhibitor PD-98059. Application of the single dose of NRG-1beta to quiescent cardiocytes induced expressional reprogramming of distinct cellular processes. This response included a prominent 50-100% increase in transcripts of multiple redox systems. It also involved a comparable mRNA augmentation of protein synthetic and folding factors together with augmented message for the trigger of cardiac hypertrophy, cyclin D1 (CCND1). First evidence for a role of neuregulin in promotion of mitochondrial turnover, voltage-gated ion channel expression, and the suppression of fatty acid transporter mRNAs was revealed. Subsequent analysis confirmed a corresponding upregulation of redox factor proteins thioredoxin and the thioredoxin reductase 1, GSTP-1, and CCND1 and demonstrated downregulation of the related transcripts by PD-98059 in neuregulin-stimulated cultures. These MAPK-dependent expressional adjustments point to novel oxidative defense and hypertrophy pathways being involved in the longer lasting protective function of neuregulin in the heart.