title: Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction.
abstract: RING-finger proteins commonly function as ubiquitin ligases that mediate protein degradation by the ubiquitin-proteasome pathway. Muscle-specific RING-finger (MuRF) proteins are striated muscle-restricted components of the sarcomere that are thought to possess ubiquitin ligase activity. We show that mice lacking MuRF3 display normal cardiac function but are prone to cardiac rupture after acute myocardial infarction. Cardiac rupture is preceded by left ventricular dilation and a severe decrease in cardiac contractility accompanied by myocyte degeneration. Yeast two-hybrid assays revealed four-and-a-half LIM domain (FHL2) and gamma-filamin proteins as MuRF3 interaction partners, and biochemical analyses showed these proteins to be targets for degradation by MuRF3. Accordingly, FHL2 and gamma-filamin accumulated to abnormal levels in the hearts of mice lacking MuRF3. These findings reveal an important role of MuRF3 in maintaining cardiac integrity and function after acute myocardial infarction and suggest that turnover of FHL2 and gamma-filamin contributes to this cardioprotective function of MuRF3.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Spencer
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Shuaib
authors.initials: S
authors.lastname: Latif
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bezprozvannaya
authors.forename: Leon
authors.initials: L
authors.lastname: de Windt
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism; D004452:Echocardiography; D064448:Filamins; D018398:Homeodomain Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008957:Models, Genetic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D003285:Contractile Proteins; C491382:Fhl2 protein, mouse; D064448:Filamins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C413644:Rnf30 protein, mouse; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases