Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice

Ross A. Breckenridge, Zia Zuberi, John Gomes, Robert Orford, Laurent Dupays, Leanne E. Felkin, James E. Clark, Anthony I. Magee, Elisabeth Ehler, Emma J. Birks, Paul J.R. Barton, Andrew Tinker, Timothy J. Mohun

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Elevated levels of the cardiac transcription factor Hand1 have been reported in several adult cardiac diseases but it is unclear whether this change is itself maladaptive with respect to heart function. To test this possibility, we have developed a novel, inducible transgenic system, and used it to overexpress Hand1 in adult mouse hearts. Overexpression of Hand1 in the adult mouse heart leads to mild cardiac hypertrophy and a reduction in life expectancy. Treated mice show no significant fibrosis, myocyte disarray or congestive heart failure, but have a greatly reduced threshold for induced ventricular tachycardia, indicating a predisposition to cardiac arrhythmia. Within 48 h, they show a significant loss of connexin43 protein from cardiac intercalated discs, with increased intercalated disc β-catenin expression at protein and RNA levels. These changes are sustained during prolonged Hand1 overexpression. We propose that cardiac overexpression of Hand1 offers a useful mouse model of arrhythmogenesis and elevated HAND1 may provide one of the molecular links between the failing heart and arrhythmia. Crown

Original languageEnglish
Pages (from-to)133-141
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume47
Issue number1
DOIs
StatePublished - Jul 2009

Keywords

  • Arrhythmogenesis
  • Connexin43
  • Hand1
  • Heart
  • Heart failure
  • Tet-on
  • Transcription factor
  • Transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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