Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Traci L. Parry, Gopal Desai, Jonathan C. Schisler, Luge Li, Megan T. Quintana, Natalie Stanley, Pamela Lockyer, Cam Patterson, Monte Willis

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)127-140
Number of pages14
JournalCardiovascular Pathology
Volume25
Issue number2
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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Keywords

  • Cardiac hypertrophy
  • Fenofibrate
  • Mitochondria
  • Myocyte
  • PPARα
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Parry, T. L., Desai, G., Schisler, J. C., Li, L., Quintana, M. T., Stanley, N., Lockyer, P., Patterson, C., & Willis, M. (2016). Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1. Cardiovascular Pathology, 25(2), 127-140. https://doi.org/10.1016/j.carpath.2015.09.008