Abstract 3341: LKB1 Gene in Myocytes Plays a Critical Role to Regulate the Coordinated Cardiac Growth and Capillary Development
Background: LKB1 gene is known as a tumor suppressor gene and its mutations are responsible for Peutz-Jeghers syndrome. LKB1 is an upstream kinase of AMP-activated protein kinase (AMPK) superfamily because it encodes a serine/threonine kinase. Therefore it has been reported that LKB1 is a key factor of energy metabolism and biological homeostasis in many tissues. However the functional role of cardiac LKB1 remains unclear. Here we developed cardiac-specific LKB1 knockout (KO) mice and investigated its cardiac phenotype.
Methods and Results: We employed male cardiac-specific LKB1 KO mice and its male littermate wild-type mice as control in this study. LKB1 KO mice exhibited atrial enlargement and ventricular hypertrophy with cardiac dysfunction. In addition, spontaneous atrial fibrillation was observed in LKB1 KO mice at 4 weeks old age. No atrial fibrosis was seen but the expression of gap junction proteins, connexin 40, 43 and 45 were decreased in atria of LKB1 KO mice. In LKB1 KO mice heart, AMPK phosphorylation was significantly reduced, and mTOR and p70S6kinase phosphorylation was increased in atria and ventricle of LKB1 KO mice. While eEF2 phosphorylation was decreased in heart of LKB1 KO mice. LKB1 silencing in cultured cardiac myocytes caused hypertrophy, which was suppressed by constitutively active form of AMPK adenovirus transfection, as well as the treatment of mTOR inhibitor, rapamycin. Moreover LKB1 KO mice exhibited the reduction of capillary density in both atria and ventricle. The mRNA and protein levels of VEGF expression were significantly diminished in both atria and ventricle of LKB1 KO mice.
Conclusion: LKB1 plays a crucial role of regulating cardiac hypertrophy through an AMPK- mTOR and eEF2 dependent manner. LKB1 also influences capillary development through an AMPK-VEGF axis, which requires for the preservation of cardiac function.