Do changes in the expression of Gαi2 affect cardiac electrophysiology?
Abstract
The heterotrimeric G protein subunit, Gαi2, is involved in signal transduction from
muscarinic acetylcholine and other receptor systems in cardiomyocytes. Gαi2
expression is elevated in human heart failure, though whether this is beneficial or
maladaptive remains unknown. Better understanding could guide therapeutics
development. Previous work with Gαi2 knockout mice suggested a pro-arrhythmic
phenotype. We hypothesised that increased Gαi2 expression is anti-arrhythmic in the
ventricles. To investigate this, an in vivo murine model of myocardial infarction was
used to approximate the human pathophysiology, with wild-type (WT) mice compared
to those with cardiospecific Gαi2 knockout. Subsequently, an ex vivo model of cardiac
tissue slices was used to evaluate normal electrophysiological properties of murine
ventricular tissue, alterations with β-adrenoceptor and muscarinic agonists and
temperature, and comparison of these properties in WT mice and those with Gαi2
globally deleted.
With the myocardial infarction model, there were no significant cardiac phenotypic
differences between cardiospecific knockouts and WTs. The cardiac slice model, which
utilised a micro-electrode array, showed stable activation and repolarisation
properties in WT slices. Comparison of WTs to Gαi2 global knockouts in the presence of
carbachol found no significant differences between groups in terms of repolarisation or
conduction properties. In WT slices, isoprenaline was associated with a small increase
in effective refractory period, but did not alter conduction properties. There was a
highly significant negative linear relationship between temperature and both
activation, and repolarisation.
Murine models were used to investigate the electrophysiological effects of autonomic
signalling pathways, and in particular, the protein Gαi2. No observable
electrophysiological differences between WT and Gαi2 knockout mice were
demonstrated. β-adrenergic agonism produced small changes in repolarisation only.
Effects of temperature on activation and refractoriness suggest modulation of sodium
and potassium currents, in keeping with published work. These findings contribute to
our understanding of autonomic modulation of murine cardiac electrophysiology
Authors
Lane, Jem Daniel HardeeCollections
- Theses [3825]