CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo

Hypertrophic growth is an adaptive response of the heart to diverse patholo gical stimuli and is characterized by cardiomyocyte enlargement, sarcomere assembly and activation of a fetal program of cardiac gene expression, A va riety of Ca2+-dependent signal transduction pathways have been implicated i n cardiac I hypertrophy bur whether these pathways are independent or inter dependent and whether there is specificity among them are unclear. Previous ly, we showed that activation of the Ca2+/calmodulin-dependent protein phos phatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo, Here, we show that activated Ca2/calmodulin-dependent protein kinases-I and -IV (CaMKI and CaMKIV) also ind uce hypertrophic responses in cardiomyocytes in vitro and that CaMKIV overe xpressing mice develop cardiac hypertrophy with increased left ventricular end-diastolic diameter and decreased fractional shortening. Crossing this t ransgenic line with mice expressing a constitutively activated form of NFAT 3 revealed synergy between these signaling pathways. We further show that C aMKIV activates the transcription factor MEF2 through a posttranslational m echanism in the hypertrophic heart in vivo. Activated calcineurin is a less efficient activator of MEF2-dependent transcription, suggesting that the c alcineurin/NFAT and CaMK/MEF2 pathways act in parallel. These findings iden tify MEF2 as a downstream target for CaMK signaling in the hypertrophic hea rt and suggest that the CaMK and calcineurin pathways preferentially target different transcription factors to induce cardiac hypertrophy.