MRC National Institute for Medical Research, London
Science for Health
Tim Mohun group project:
HAND1 in heart homeostasis
Hand1, a basic helix-loop-helix transcription factor, is expressed at high levels in the embryonic heart, with a precipitates drop in expression at birth. In humans and rodents, there is evidence that the level of Hand1 transcription is altered in cardiac disease.For example, left ventricular biopsies from patients with hypertrophic cardiomyopathy and tetralogy of Fallot have revealed elevated levels of HAND1 mRNA expression. To test whether elevated Hand1 expression may be maladaptive in heart failure, we have used a binary inducible (tet-on) system to upregulate Hand1 in the adult myocardium.
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Induction of a lacZ transgene in myocardial muscle of the mouse heart (A); magnification of ventricular wall (B) and pulmonary veins (C); similar induction in the embryo (D).
This results in a phenotype resembling some aspects of human heart failure. The mice exhibit sudden cardiac death, a lengthened QTc and electrophysiological changes, including a low threshold for ventricular tachycardia (VT), resulting in sudden death. The molecular basis of this is likely to include remodelling of the cardiac end-plate, detected after 24 hours of Hand1 induction. Changes include downregulation of Connexin43 (Cx43) protein, and accumulation of ß-catenin protein, both seen in human heart failure/cardiomyopathy (see Breckenridge, RA et. al., 2009).
Survival of Hand1 overexpressing mice is sharply reduced compared with controls
Hand1 upregulating mice also exhibit alterations in energy metabolism reminiscent of those (such as decreased lipid ß-oxidation) seen in human heart failure. The inducible Hand1 mouse may therefore provide a model for studying wider molecular changes underlying the heart failure phenotype. We are using microarray analysis from the mouse model and cultured cardiomyocytes to investigate the changes triggered by Hand1 and the relative contributions of changed energy status, ß-catenin levels and direct transcriptional regulation by Hand1 in the heart failure-like phenotype.
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Changes in mouse Hand1 and PPAR gene expression at birth
Of particular interest is the observation that the dramatic fall in Hand1 expression at birth coincides both with a switch in cardiac energy metabolism (from glycolysis to ß-oxidation of lipid) and the onset of remodeling of cardiomyocyte conductivity. Intriguingly, there is evidence of reverse changes in response to hypoxia. We aim to test the possibility that coordinate regulation of both energy metabolism and electrophysiology of the heart is influenced by hypoxic signalling in both normal development (birth) and heart failure.
Collaborators
- Ross Breckenridge MA MRCP PhD, UCH; Andrew Tinker, UCL
Mohun group
Recent publications
Research projects
- Nkx2-5 transcriptional targets
- Down syndrome cardiac defects
- Ventricular compaction and disease
- HAND1 in heart homeostasis
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