Transcriptional effects of E3 ligase atrogin-1/MAFbx on apoptosis, hypertrophy and inflammation in neonatal rat cardiomyocytes

PLoS One. 2013;8(1):e53831. doi: 10.1371/journal.pone.0053831. Epub 2013 Jan 15.

Abstract

Atrogin-1/MAFbx is an ubiquitin E3 ligase that regulates myocardial structure and function through the ubiquitin-dependent protein modification. However, little is known about the effect of atrogin-1 activation on the gene expression changes in cardiomyocytes. Neonatal rat cardiomyocytes were infected with adenovirus atrogin-1 (Ad-atrogin-1) or GFP control (Ad-GFP) for 24 hours. The gene expression profiles were compared with microarray analysis. 314 genes were identified as differentially expressed by overexpression of atrogin-1, of which 222 were up-regulated and 92 were down-regulated. Atrogin-1 overexpression significantly modulated the expression of genes in 30 main functional categories, most genes clustered around the regulation of cell death, proliferation, inflammation, metabolism and cardiomyoctye structure and function. Moreover, overexpression of atrogin-1 significantly inhibited cardiomyocyte survival, hypertrophy and inflammation under basal condition or in response to lipopolysaccharide (LPS). In contrast, knockdown of atrogin-1 by siRNA had opposite effects. The mechanisms underlying these effects were associated with inhibition of MAPK (ERK1/2, JNK1/2 and p38) and NF-κB signaling pathways. In conclusion, the present microarray analysis reveals previously unappreciated atrogin-1 regulation of genes that could contribute to the effects of atrogin-1 on cardiomyocyte survival, hypertrophy and inflammation in response to endotoxin, and may provide novel insight into how atrogin-1 modulates the programming of cardiac muscle gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Cardiomegaly / genetics*
  • Cell Proliferation
  • Cluster Analysis
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Inflammation / genetics*
  • Metabolic Networks and Pathways / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology*
  • NF-kappa B / metabolism
  • Rats
  • Reproducibility of Results
  • SKP Cullin F-Box Protein Ligases / genetics*
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction

Substances

  • Muscle Proteins
  • NF-kappa B
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases
  • Mitogen-Activated Protein Kinases

Grant support

This study was supported by grants from the China Natural Science Foundation (81025001, 30971097 and 30888004), the Beijing High-Level Talents Program (PHR20110507). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.