Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

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• 作者：Traci L. Parry^a ; ¹ ; Gopal Desai^b ; ¹ ; Jonathan C. Schisler^a ; ^c ; Luge Li^d ; Megan T. Quintana^e ; Natalie Stanley^f ; Pamela Lockyer^d ; Cam Patterson^a ; ^g ; Monte S. Willis^a ; ^c ; ^d ; ^{monte_willis@med.unc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ANP ; atrial natriuretic peptide ; apoA-I ; apolipoprotein A-I ; apoA-II ; apolipoprotein A-I ; APOH ; apolipoprotein H ; βMHC ; beta-myosin heavy chain ; MYH7 ; myosin heavy chain 7 ; BNP ; brain natriuretic peptide ; cJun ; Jun proto-oncogene ; cMyBP-c ; cardiac myosin binding protein-c ; Col1A ; collagen ; type I ; alpha I ; cpt1 ; carnitine palmitoyltransferase 1A ; cTnI ; cardiac troponin I ; CSTA ; cystatin A ; DAVID ; Database for Annotation ; Visualization and Integrated Discovery ; E2F-1/E2F1 ; E2F transcription facto
• 刊名：Cardiovascular Pathology
• 出版年：2016
• 出版时间：March-April 2016
• 年：2016
• 卷：25
• 期：2
• 页码：127-140
• 全文大小：2206 K

文摘

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.