In response to pathophysiologic stress the adult heart undergoes hypertrophic growth characterized by an increase in individual myofiber size. Release of neural-humoral factors regulate cardiomyocyte hypertrophy through membrane bound growth factor receptors, which in turn activate intermediate signal transduction pathways such as mitogen-activated protein kinases (MAPK), protein kinase C (PKC), and calcineurin. In general, three branches comprise the MAPK signaling pathway (ERKs, JNKs and p38), each of which has been implicated in regulating cardiac hypertrophv or apoptosis in cultured cardiomyocytes. However, very little investigation has been extended in vivo. Accordingly, here we propose an indepth analysis of the extracellular signal-regulate kinases 1/2 (ERK 1/2) as effectors of cardiac hypertrophy and apoptosis in genetically altered mouse models. Specifically, we will test the hypotheses that ERK1 /2 signaling is necessary for regulating cardiac hypertrophy in vivo, and that ERK 1/2 signaling protects the heart during ischemiareperfusion induced cellular apoptosis. To this end, transgenic mice expressing dominant negative MEK1 in the heart have been generated, and ERK1 and ERK2 single gene knock-out mice have been otained and a colony extablished for analysis.
| Purcell, Nicole H; Darwis, Dina; Bueno, Orlando F et al. (2004) Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. Mol Cell Biol 24:1081-95 |
