Abstract 16847: Cardiac Deletion of Liver Kinase B1 Leads to Cardiac Dysfunction, Atrial Arrhythmias and Ultra-Structural Abnormalities That are Not Attributable to AMP-Activated Protein Kinase Inactivation
Liver kinase B1 (LKB1) is an upstream activator of AMP-activated protein kinase (AMPK) as well as 12 other members of the AMPK superfamily. In order to address the potential role of LKB1/AMPK signaling in cardiac development and growth, we generated cardiac specific LKB1 deleted mice (MHC Cre-LKB1flox/flox) in a pure C57/Bl6 background and compared cardiac size, function, electrophysiology and ultra-structure to syngeneic AMPK kinase-dead (AMPK-KD) mice expressing the rat alpha2 K45R mutation. LKB1 mRNA and protein were reduced by >85% in atria and >95% in ventricles in MHC Cre-LKB1flox/flox hearts. MHC Cre-LKB1flox/flox (n = 6) mice were in sinus rhythm at postnatal day 1, but developed atrial fibrillation by two weeks of age (n = 11); in contrast, LKB1flox/flox (n = 5) and AMPK-KD (n = 6) mice did not develop atrial arrhythmias through 10 weeks. Echocardiography revealed significant left atrial (LA) enlargement by 4 weeks of age (1.95 ± 0.11 mm vs. 1.45 ± 0.19 mm, p<0.05), left ventricle (LV) hypertrophy at 6 weeks of age (0.78 ± 0.03 mm vs. 0.67 ± 0.03 mm, p<0.05), and progressive cardiac dysfunction (LV ejection fraction (LVEF): 40.3 ± 2.1% vs. 48.9 ± 2.3%) in MHC Cre-LKB1flox/flox vs. LKB1flox/flox. In contrast, AMPK-KD (n = 6) vs. AMPK-WT (n = 3) hearts had similar LA diameter (1.51 ± 0.15 mm vs. 1.59 ± 0.05 mm), LV wall thickness (0.67 ± 0.03 mm vs. 0.66 ± 0.03 mm), and LVEF (48.9 ± 2.3% vs 47.8 ± 2.4%). Histological analysis revealed marked atrial fibrosis by two weeks of age in MHC Cre-LKB1flox/flox hearts, but normal morphology in AMPK-KD hearts through 10 weeks. Electron microscopy showed disrupted gap junction formation, mitochondrial integrity and the presence of autophagic bodies exclusively in MHC Cre-LKB1flox/flox hearts. In conclusion, this study indicates marked myopathic and arrhythmic abnormalities in LKB1 deleted vs. AMPK-KD mouse hearts. Thus, AMPK-independent signaling, possibly mediated by AMPK-related kinases, appear to be critical for LKB1 regulated cardiac development and growth.
- © 2011 by American Heart Association, Inc.