Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction

Jens Fielitz, Eva Van Rooij, Jeffrey A. Spencer, John M. Shelton, Shuaib Latif, Roel Van Der Nagel, Svetlana Bezprozvannaya, Leon De Windt, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

69 Scopus citations

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 γ-filamin proteins as MuRF3 interaction partners, and biochemical analyses showed these proteins to be targets for degradation by MuRF3. Accordingly, FHL2 and γ-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 γ-filamin contributes to this cardioprotective function of MuRF3.

Original languageEnglish (US)
Pages (from-to)4377-4382
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number11
DOIs
StatePublished - Mar 13 2007

Keywords

  • Cardiac stress response
  • Heart failure
  • Protein degradation
  • Sarcomere

ASJC Scopus subject areas

  • General

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