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Expressional reprogramming of survival pathways in rat cardiocytes by neuregulin-1beta
Marie-Noëlle Giraud1, Martin Flück, Christian Zuppinger
1Swiss Cardiovascular Center, Bern, Switzerland.
Abstract:
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.
Insights
Neuregulin-1beta (NRG-1beta) promotes heart cell survival by upregulating redox systems and protein synthesis pathways. This growth factor also influences mitochondrial turnover and cardiac hypertrophy, revealing new protective mechanisms.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Muscle Physiology
Background:
- Neuregulin/ErbB2 signaling is crucial for heart and skeletal muscle survival.
- Understanding neuregulin-dependent pathways is key to muscle cell protection.
- The transcript targets of neuregulin in cardiocytes are largely uncharacterized.
Purpose of the Study:
- To map the transcript targets of neuregulin-1beta (NRG-1beta) in adult rat cardiocytes.
- To elucidate the regulatory pathways involved in neuregulin-mediated muscle cell survival.
- To identify novel NRG-1beta-induced cellular processes in the heart.
Main Methods:
- Adult primary rat cardiocytes were treated with recombinant human NRG-1beta.
- Transcriptional changes were analyzed using cDNA arrays and L1 regression analysis.
- Key findings were validated by RT-PCR, Western blotting, and MAPK pathway inhibition (PD-98059).
Main Results:
- NRG-1beta treatment significantly increased transcripts for redox systems and protein synthesis factors.
- Upregulation of cyclin D1 (CCND1), a trigger for cardiac hypertrophy, was observed.
- Evidence suggests NRG-1beta influences mitochondrial turnover, ion channel expression, and fatty acid transport.
Conclusions:
- NRG-1beta induces expressional reprogramming in cardiocytes, enhancing oxidative defense and protein synthesis.
- MAPK-dependent pathways are involved in NRG-1beta's protective effects on the heart.
- These findings reveal novel mechanisms underlying neuregulin's long-lasting protective function in cardiac tissue.
