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Potential mechanisms of cardiac hypertrophy in mice with a null deletion of MAFbx (1164.7)
Author(s) -
Matern Philip,
Gomes Aldrin,
Bodine Sue
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1164.7
Subject(s) - ubiquitin ligase , ubiquitin , proteasome , heart failure , medicine , protein kinase b , endocrinology , cardiomyopathy , protein degradation , ejection fraction , phosphorylation , protein subunit , chemistry , biology , microbiology and biotechnology , biochemistry , gene
The E3 ubiquitin ligase, MAFbx, has been shown to target specific proteins for degradation through poly‐ubiquitination and the ubiquitin proteasome system. A null deletion of MAFbx reveals no cardiac phenotype in young unchallenged knock out (KO) mice, but leads to the development of congestive heart failure and sudden death (at 18 months) in unchallenged aging mice. The aim of this study was to determine potential mechanisms underlying the development of congestive heart failure in MAFbx KO animals. Echocardiograms demonstrated functional changes (reduced fractional shortening and left ventricular ejection fraction) in KO animals beginning at 11 months and markers for multiple growth pathways were elevated in KO mice at 14 months of age. Calcineurin expression was elevated above wildtype (WT) at 14 months and remained elevated at 18 months. Phosphorylated Akt (S473) and GSK3β (S9) expression were also elevated at 14 months. Markers of the proteasome system demonstrated altered expression and activity relative to WT animals. Expression of 19 and 20S proteasome subunits (RPT1, α3, β5) were elevated in KO mice at 14 months, but only the 26S β1 subunit showed higher activity, with no change in β2 or β5 activity. The 14 month mice also had elevated total ubiquitinated proteins and reduced free ubiquitin. Together, these findings suggest that MAFbx deletion results in a progressive disruption of protein quality control (increased protein synthesis and limited increase in protein degradation) leading to activation of pathological signaling pathways and the development of cardiomyopathy. Grant Funding Source : Muscular Dystrophy Association