Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice.
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 beta-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.
Breckenridge
Ross A
RA
MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. rbrecke@nimr.mrc.ac.uk
Zuberi
Zia
Z
Gomes
John
J
Orford
Robert
R
Dupays
Laurent
L
Felkin
Leanne E
LE
Clark
James E
JE
Magee
Anthony I
AI
Ehler
Elisabeth
E
Birks
Emma J
EJ
Barton
Paul J R
PJ
Tinker
Andrew
A
Mohun
Timothy J
TJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D004594:Electrophysiology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051792:Basic Helix-Loop-Helix Proteins; C095572:Hand1 protein, mouse; C097341:helix-loop-helix protein, eHAND