title: Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1.
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.
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Parry
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Desai
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Luge
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Quintana
authors.affiliation: Department of Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Stanley
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockyer
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.|Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000172:deficiency / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D000070584:Tripartite Motif Proteins / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000960:Hypolipidemic Agents; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011345:Fenofibrate
keywords: Cardiac hypertrophy; Fenofibrate; Mitochondria; MuRF1; Myocyte; PPARα; Ubiquitin ligase