Abstract 538: Differential Regulation of MEF2-dependent Gene Transcription in Endothelial Cells by G12/G13 Proteins
Members of myocyte-specific enhancer factor 2 (MEF2) proteins are important for cardiac and vascular development. Mutation of MEF2A was suggested as a cause for coronary artery disease. Since heterotrimeric G13 but not G12 protein is also required for vascular development, we tested the hypothesis that G13 but not G12 mediates a novel signaling pathway in MEF2-dependent gene transcription. We demonstrated that the alpha subunit of G13 protein could stimulate MEF2-dependent gene transcription. Down-regulation of endogenous Ga13 and Ga12 in human umbilical vein endothelial cells (HUVECs) showed that Ga13 was required for thrombin stimulated MEF2-dependent gene transcription. Stimulation of MEF2-dependent gene transcription by a constitutively activated Ga13 (Ga13Q226L) was inhibited by dominant negative mutant of Ca2+/calmodulin-dependent kinase IV (CaMKIV). Furthermore, Ga13Q226L but not Ga12Q229L was able to increase Ca2+/calmodulin-independent CaMKIV activity. In addition Ga13Q226L but not Ga12Q229L was able to induce the translocation of histone deacetylase 5 (HDAC5) from nucleus to cytoplasm. Repression of MEF2C mediated gene transcription by HDAC4 and HDAC5 was abolished by Ga13Q226L not by Ga12Q229L. In conclusion, our studies establish a link between G13 and MEF2C, two regulators of endothelial cell development.