Ankyrin-B protein in heart failure: Identification of a new component of metazoan cardioprotection

Farshid Kashef, Jingdong Li, Patrick Wright, Jedidiah Snyder, Faroug Suliman, Ahmet Kilic, Robert Higgins, Mark Anderson, Philip F. Binkley, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticle

Abstract

Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, βII-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.

Original languageEnglish (US)
Pages (from-to)30268-30281
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number36
DOIs
StatePublished - Aug 31 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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