Induction of Simultaneous Downregulation of Myocardial E3 Ligases in Ischemic Heart Failure

 

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Objectives: Heart failure (HF), developing after a myocardial infarction (MI), is associated with cardiac remodeling and aerobic exercise training (AET) seems to counteract these effects. The ubiquitin proteasome system (UPS) is one of the major system involved in these remodeling processes, but data on UPS in established HF animal models and the timely activation are rare. The present study investigated different components of the left ventricular myocardial UPS 3 days after an MI and after the development of HF. Furthermore, the effect of AET on HF-induced UPS changes was analyzed.

Methods: Mice were assigned to the following groups: sham operation (n = 10), LAD ligation 3 days (n = 10), LAD ligation 10 weeks (n = 10), LAD ligation 10 weeks + AET (n = 10). AET was started 1 week after LAD ligation. HF was confirmed by echocardiography. Expression levels of myocardial E3 ligases (CHIP, ITCH, MAFbx/atrogin, MuRF1, Mdm2), deubiquitinases (DUBs; A20, CYLD, UCH-L1, USP14, USP19) and of BAG3 were determined by qPCR and Western Blot. The proteasomal activity of different catalytic domains was determined.

Results: HF significantly decreased E3 ligase expression 3 days (CHIP p = 0.030, ITCH p = 0.890, MAFbx p = 0.002, MuRF1 p = 0.008, Mdm2 p = 0.034) and 10 weeks after LAD ligation (CHIP p = 0.004, ITCH p = 0.020, MAFbx p = 0.121, MuRF1 p = 0.027, Mdm2 p = 0.028). Except for USP19, which showed a decreased expression at 3 days (p = 0.008) and 10 weeks (p = 0.005), the expression of DUBs remained unaffected after MI and induction of HF. BAG3, which is involved in protein degradation, is decreased after 3 days (p = 0.017) and showed a trend to decrease until 10 weeks following HF induction (p = 0.066). The proteasomal activity of the trypsin-, chymotrypsin- and caspase-like domain did not change after 3 days and up to 10 weeks when compared with the controls. Furthermore, AET attenuated the effects induced by HF with the exceptions of CHIP.

Conclusion: E3 ligase expression changes significantly in HF mice. Except USP19, DUB expression was unaffected in the HF-damaged myocardium. The unaltered proteasome activity indicates that the proteasome itself is not sufficient as the primary target to regulate cardiac remodeling. The decreased BAG3 expression suggested that beside the UPS further cellular systems involved in protein degradation are downregulated in ischemic HF. Additionally, the importance of AET as therapeutic approach in HF should be considered in future studies.