TY - JOUR
T1 - Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice
AU - Breckenridge, Ross A.
AU - Zuberi, Zia
AU - Gomes, John
AU - Orford, Robert
AU - Dupays, Laurent
AU - Felkin, Leanne E.
AU - Clark, James E.
AU - Magee, Anthony I.
AU - Ehler, Elisabeth
AU - Birks, Emma J.
AU - Barton, Paul J.R.
AU - Tinker, Andrew
AU - Mohun, Timothy J.
PY - 2009/7
Y1 - 2009/7
N2 - 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
AB - 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
KW - Arrhythmogenesis
KW - Connexin43
KW - Hand1
KW - Heart
KW - Heart failure
KW - Tet-on
KW - Transcription factor
KW - Transgenic
UR - http://www.scopus.com/inward/record.url?scp=67349229548&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349229548&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2009.04.007
DO - 10.1016/j.yjmcc.2009.04.007
M3 - Article
C2 - 19376125
AN - SCOPUS:67349229548
SN - 0022-2828
VL - 47
SP - 133
EP - 141
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 1
ER -
