Transcriptional upregulation of calcineurin Abeta by endothelin-1 is partially mediated by calcium/calmodulin-dependent protein kinase IIdelta3 in rat cardiomyocytes.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) are positive regulators of cardiac hypertrophy, but the nature of cross-talk between CaMKII and CaN signaling pathways in hypertrophic cardiomyocytes remains unclear. Here we documented that CaMKIIdelta3 activation enhances transcription of the CaN gene through activation of the CaN-Abeta subunit (CnAbeta) promoter in rat cultured cardiomyocytes. Co-immunoprecipitation assays showed that MEF2 forms a complex with GATA4 following transfection of an active CaMKIIdelta3 (T278D) mutant in neonatal cardiomyocytes. Inversely, transfection of a dominant negative CaMKIIdelta3 mutant failed to promote a MEF2-GATA4 complex. Consistent with these observations, immunocytochemistry indicated nuclear co-localization of MEF2 with GATA4 after hypertrophic agonist stimulation or CaMKIIdelta3 (T278D) transfection. These data demonstrate that CaMKII can enhance CnAbeta promoter activity by enhancing MEF2-GATA4 synergy, suggesting a novel mechanism for CaMKII-mediated hypertrophic signaling, which contributes to induction and development of the hypertrophic response through CaN activation.
Lu
Ying-Mei
YM
Department of Pharmacology, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
Shioda
Norifumi
N
Yamamoto
Yui
Y
Han
Feng
F
Fukunaga
Kohji
K
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D019703:Calcineurin / Q000235:genetics*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D050991:GATA4 Transcription Factor / Q000378:metabolism; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D017931:DNA Primers; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin