Atrophic remodeling of the transplanted rat heart.

Abstract

We have previously shown that the common feature of both pressure overload-induced hypertrophy and atrophy is a reactivation of the fetal gene program. Although gene expression profiles and signal transduction pathways in pressure overload hypertrophy have been well studied, little is known about the mechanisms underlying atrophic remodeling of the unloaded heart. Here, we induced atrophic remodeling by heterotopic transplantation of the rat heart. The activity parameters of three signal transduction pathways important in hypertrophy, i.e. mitogen-activated protein (MAP) kinase, mammalian target of rapamycin (mTOR), and Janus kinase/signal transducers and activators of transcription (JAK/STAT), were interrogated. Gene expression of upstream stimuli--insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2)--and metabolic correlates, i.e. peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated genes, of these pathways were also measured. In addition, we measured transcript levels of genes known to regulate skeletal muscle atrophy, all of which are negatively regulated by IGF-1 (Mafbx/Atrogin-1, MuRF-1). Atrophic remodeling of the heart was associated with increased expression of IGF-1 and FGF-2. Transcript levels of the nuclear receptor PPARalpha were decreased, as were the levels of PPARalpha-regulated genes. Furthermore, there was phosphorylation of ERK1, STAT3, and p70S6K with unloading. Consistent with the increase in IGF-1, we found a decrease in Mafbx/Atrogin-1 and MuRF-1 transcript levels. Rapamycin administration at 0.8 mg/kg/day for 7 days resulted in enhanced atrophy and attenuated the phosphorylation of ERK1, STAT3, and p70S6K without altering gene expression. We conclude that there is significant crosstalk between the mTOR, MAP kinase, and JAK/STAT signaling cascades. Furthermore, ubiquitin ligases, known to be essential for skeletal muscle atrophy, decrease in unloading-induced cardiac atrophy.

• Authors: Saumya Sharma, Jun Ying, Peter Razeghi, Stanislaw Stepkowski, Heinrich Taegtmeyer
• Journal: Cardiology (Cardiology) Vol. 105 Issue 2 Pg. 128-36 ( 2006) ISSN: 0008-6312 [Print] Switzerland
• PMID: 16391472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2006 S. Karger AG, Basel.

Chemical References

• PPAR alpha
• Fibroblast Growth Factor 2
• Insulin-Like Growth Factor I
• Ubiquitin-Protein Ligases
• Mitogen-Activated Protein Kinases
• Sirolimus

Topics

• Animals
• Atrophy (genetics, physiopathology)
• Fibroblast Growth Factor 2 (metabolism)
• Gene Expression Profiling
• Heart (drug effects)
• Heart Transplantation
• Insulin-Like Growth Factor I (metabolism)
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardium (metabolism, pathology)
• PPAR alpha (metabolism)
• Rats
• Rats, Wistar
• Sirolimus (pharmacology)
• Ubiquitin-Protein Ligases (metabolism)
• Ventricular Remodeling (drug effects, genetics, physiology)