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.
Highlights
Heart failure (HF) is the final and common pathway for various cardiovascular diseases
To identify genes differentially regulated by atrogin-1 in cardiomyocytes, we examined the changes in the gene expression profiles of cardiomyocytes infected by adenovirus atrogin-1 (Adatrogin-1) and green fluorescent protein (GFP) control (Ad-GFP) using DNA microarray assay
The analysis showed a clear separation of the Ad-GFP control (G) and overexpressed atrogin-1 (A) groups, when a clustering was performed on a subset of genes that displayed different expression with fold changes $2-fold or #22-fold (Figure 1C)
Summary
Heart failure (HF) is the final and common pathway for various cardiovascular diseases. Several studies demonstrated that LPS directly induces cardiomyocyte hypertrophy, apoptosis and depresses contractility, leading to cardiomyopathy and congestive heart failure [3]. Disturbances in the ubiquitin-proteasome system are thought to be involved in the development of various cardiovascular diseases, including HF, cardiac infarction and atherosclerosis [4,5,6,7,8]. A study has identified two novel ubiquitin E3 ligases, atrogin-1/MAFbx and MuRF1, which function as negative regulator of muscle cell size in vitro and in vivo [5,6,9,10,11,12]
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