Abstract 937: Cardiac Developmental Defects and Spontaneous Eccentric Right Ventricular Hypertrophy in Cardiomyocyte FAK Conditional Knockout Mice
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in integrin-mediated signal transduction. The interactions of cardiomyocytes with their surrounding extracellular matrix through integrin are important for cardiac development and maturation. To explore the role and mechanisms of FAK in cardiac development, we inactivated FAK in embryonic cardiomyocytes by crossing the floxed FAK mice with myosin light chain-2a (MLC2a) Cre mice. MLC2a-Cre expressed as early as E9.5 and expressed in the whole heart, including both ventricles and atria. The majority of conditional FAK knockout mice generated from MLC2a-Cre (CFKO-2a) died in the embryonic stage with thin ventricular wall and ventricular septal defects. A small fraction of CFKO-2a mice survived to adulthood with spontaneous eccentric right ventricle hypertrophy. Transmission electronic microscopy analysis displayed the swelling in the rough endoplasmic reticulum in CFKO-2a embryonic cardiomyocytes. We found that decreased cell proliferation, but not increased cell apoptosis and differentiation, is the reason for the thin ventricular wall in CFKO-2a mice. Microarray analysis suggests that myocyte enhancer factor 2a (MEF2a) can be regulated by FAK, and inactivation of FAK in embryonic heart compromised the MEF2a expression. Lastly, we found that Src, but not PI3K, mediated signal transduction is important for the regulation of MEF2a by FAK. Together, these results identified the role and mechanisms of FAK in embryonic cardiac development.