Format

Send to

Choose Destination
Cardiovasc Pathol. 2016 Mar-Apr;25(2):127-140. doi: 10.1016/j.carpath.2015.09.008. Epub 2015 Oct 29.

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1.

Author information

1
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
2
Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
3
Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
4
Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
5
Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
6
Department of Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
7
Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA.
#
Contributed equally

Abstract

The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1-/- mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1+/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1-/- mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1-/- genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <-4 log fold change; P ≤ .0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis.

KEYWORDS:

Cardiac hypertrophy; Fenofibrate; Mitochondria; MuRF1; Myocyte; PPARα; Ubiquitin ligase

PMID:
26764147
PMCID:
PMC4754579
[Available on 2017-03-01]
DOI:
10.1016/j.carpath.2015.09.008
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center