Dysfunction of the β2-spectrin-based pathway in human heart failure

Sakima A. Smith, Langston D. Hughes, Crystal F. Kline, Amber N. Kempton, Lisa E. Dorn, Jerry Curran, Michael Makara, Tyler R. Webb, Patrick Wright, Niels Voigt, Philip F. Binkley, Paul M.L. Janssen, Ahmet Kilic, Cynthia A. Carnes, Dobromir Dobrev, Matthew N. Rasband, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticlepeer-review

Abstract

β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic-and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca2+-and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca2+-and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca2+-and calpain-dependent proteolysis.

Original languageEnglish (US)
Pages (from-to)H1583-H1591
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number11
DOIs
StatePublished - Jun 2016
Externally publishedYes

Keywords

  • Arrhythmias/cardiac
  • Cytoskeleton
  • Ion channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Dysfunction of the β<sub>2</sub>-spectrin-based pathway in human heart failure'. Together they form a unique fingerprint.

Cite this