Cardiac-Specific Activation of @entity28293 Leads to Defects in Heart Development and XXXX .

@entity32 @entity2085 @entity19 @entity28293 @entity25844
UNASSIGNED: The transcription factor NF-kB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of @entity32 and pro-survival factor. Here, we addressed the question what effects activation of NF-kB can have during @entity19 heart development. We expressed a constitutively active (CA) mutant of @entity28293 , the kinase activating canonical NF-kB signaling, specifically in cardiomyocytes under the control of the a-myosin heavy chain promoter. Expression of @entity28293 -CA resulted in @entity2085 around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread @entity32 with infiltration of myeloid cells. Gene expression analysis suggested an interferon type I signature, with increased expression of interferon regulatory factors. While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation. Mechanistically, this could be explained by activation of the JAK/STAT axis and increased expression of the cell cycle inhibitor @entity25844 . A rescue experiment with an IkBa superrepressor demonstrated that the phenotype was dependent on NF-kB. We conclude that activation of NF-kB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.
