Abstract 17145: Ventricular-Specific Deletion of Liver Kinase B1 Fails to Produce Cardiomyopathy and Atrial Fibrillation Associated with Pan-Cardiac Deletion of Liver Kinase B1

Abstract

Liver kinase B1 (LKB1) is a serine/threonine kinase that is the major upstream kinase for AMP-activated protein kinase, but also appears to have additional actions regulating cardiac growth and development. In order to assess the functional consequences of LKB1 deletion on ventricular structure and function, we compared pan-cardiac LKB1 knockout (MHC Cre-LKB1flox/flox) with ventricular-specific LKB1 knockout (MLC2v Cre-LKB1flox/flox) and control mice (LKB1flox/flox). LKB1 mRNA was reduced by 91% in MHC Cre-LKB1flox/flox ventricles and 84% in MLC2v Cre-LKB1flox/flox ventricles; LKB1 protein was reduced by 95% in both RV and LV from MHC Cre-LKB1flox/flox mice and by 87% in MLC2v Cre-LKB1flox/flox mice. LKB1 expression in left atrial (LA) was normal in MLC2v Cre-LKB1flox/flox, but was reduced by 85% in MHC Cre-LKB1flox/flox. MHC Cre- LKB1flox/flox mice developed early onset atrial fibrillation (2 weeks) in contrast to MLC2v Cre-LKB1flox/flox and control hearts, which showed no arrhythmia. MHC Cre-LKB1flox/flox hearts had LA enlargement vs. MLC2v Cre-LKB1flox/flox vs. LKB1flox/flox (2.53±0.13 mm vs. 1.59±0.21 mm vs.1.61±0.12 mm, n=5-11, p<0.05). In addition, left ventricular (LV) wall thickness was greater (p<0.05) in MHC Cre-LKB1flox/flox (0.91±0.03 mm) vs. MLC2v Cre-LKB1flox/flox (0.71±0.02 mm) vs. LKB1flox/flox (0.69±0.02 mm, p<0.05). MHC Cre-LKB1flox/flox also had decreased LV ejection fraction (LVEF) of 30.9±1.5% vs. MLC2v Cre-LKB1flox/flox (48.5±2.7%) vs. LKB1flox/flox (46.8±3.1%, p<0.05). Electron micrographs of MHC Cre-LKB1flox/flox ventricles showed alterations in gap junction formation and a loss of mitochondrial integrity; however, both MHC Cre-LKB1flox/flox and MLC2v Cre-LKB1flox/flox hearts appeared normal. Thus, pan-cardiac deletion of LKB1 leads to atrial fibrillation, LV hypertrophy and LV dysfunction, which do not occur with ventricular specific LKB1 deletion.