The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy.
Pathologic cardiac hypertrophy imposes a significant clinical burden on patients, yet the precise intracellular mechanisms responsible for its induction are only partially understood. We examined a potential role for AKAP121 to regulate cardiomyocyte hypertrophy, since recent reports have implicated other AKAPs in this process. We report here that knockdown of AKAP121 expression in isolated neonatal rat cardiomyocytes results in pronounced cellular hypertrophy. Loss of AKAP121 expression is associated with dephosphorylation and nuclear localization of NFATc3, a downstream effector of the hypertrophic phosphatase calcineurin. We also demonstrate that over-expression of AKAP121 in cardiac myocytes reduces basal cell size, and blocks hypertrophy induced by isoproterenol, indicating that AKAP121 negatively regulates the hypertrophic process. Co-immunoprecipitation data indicates that AKAP121 and calcineurin directly interact. Our findings are consistent with a model in which loss of AKAP121 expression leads to the release of an active pool of calcineurin, in turn causing nuclear translocation of NFATc3 and activation of the hypertrophic gene program. These results are the first to identify AKAP121 as a negative regulator of cardiomyocyte hypertrophy, and highlight AKAP121 as a potential target for therapeutic exploitation.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba R2H2A6, Canada.
Bernard
B
Abrenica
Mohamed
M
AlShaaban
Michael P
MP
Czubryt
D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D055785:Gene Knockdown Techniques; D006984:Hypertrophy; D008954:Models, Biological; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C486332:Akap1 protein, rat; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; C445503:transcription factor NF-AT c3