Key result
JDP2 expression in mouse hearts drives massive reversible biatrial dilatation and AV conduction defects.
Why the study?
The role of specific bZIP transcription factors in cardiac development and function remains unclear due to embryonic lethality and functional compensation in knockout models.
bZIP inhibition by JDP2 causes reversible postnatal atrial dilatation and conduction defects in mice, suggesting bZIP repressors as potential targets for preventing atrial dilatation and atrial fibrillation.
Hypothesis-generating for bZIP-targeted AF therapies in mice; should not yet change clinical practice.
Accumulating evidence suggests that nuclear transcription factors from the basic leucine zipper (bZIP) family play an important role in cardiac development and function. This class includes the CREB/ATF family of transcription factors, namely CREB, cAMP response element modulator (CREM), ATF, and the related AP-1 and C/EBP families. An effort has been made to elucidate the role of specific bZIP members in the heart. Unfortunately, little insight could be gained from knockout experiments, either due to embryonic lethal phenotypes or functional compensation by other bZIP family members. Surprisingly, cardiac overexpression of several inhibitory transcription factors from the bZIP family, such as a nonphosphorylatable form of CREB (CREB(ser133)), a nonfunctional isoform of CREM, or ATF3 resulted in massive atrial dilatation. In order to try and characterize this pathway we have expressed the potent bZIP inhibitory protein, Jun dimerization protein 2 (JDP2), specifically in the mouse heart in a temporally controlled manner. Expression of JDP2 resulted in massive biatrial dilatation; loss of connexin 40 (Cx40), connexin43 (Cx43), and myosin light chain 2 (MLC2a) expression; atrioventricular defects in conduction; and a lethal phenotype. All these effects were independent of any developmental events acquired during adulthood, and were totally reversible upon abolishing the bZIP inhibition. The results of this article suggest that bZIP inhibition is sufficient to cause atrial dilation, that this dilatation is acquired postnatally, and that it is reversible upon the relief of inhibition. Thus, bZIP repressors may serve as novel drug targets for the prevention of atrial dilatation a major risk of atrial fibrillation (AF).
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Kehat et al. (2006) studied Myocardial hypertrophy and atrial dilatation. Expression of Jun dimerization protein 2 (JDP2) was evaluated on Atrial dilatation and phenotypic changes. Expression of the bZIP inhibitory protein JDP2 in the mouse heart resulted in massive, reversible biatrial dilatation, loss of connexin expression, and atrioventricular conduction defects.
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