P288Reactivating DNA replication in the differentiated mammalian cardiomyocyte: A role for Ciz1

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Abstract

Sustained injury of the myocardium leads ultimately to heart failure. Restricted ability of the heart to repair after injury is due to inherent limited regenerative capacity of the bi-nucleated adult cardiomyocyte. A long sought goal has therefore been to identify approaches that facilitate cardiomyocyte proliferation and regeneration.

CDKN1A interacting zinc finger protein 1 (Ciz1) is a novel alternatively spliced gene that has been shown to play a role in mammalian DNA replication in vitro. All mammalian cell lines tested to date express at least one isoform of Ciz1, including differentiated cells and embryonic stem cells. In vivo, expression is predominantly full length and can be detected throughout embryonic development as well as in many adult tissues. Full length Ciz1 protein localises to dynamic sub-nuclear foci, with co-localisation experiments suggesting significant association with DNA replication factories and active DNA synthesis. Ciz1 has also been found to interact directly with key regulators of the cell cycle, including cdk2, cyclin E and cyclin A, and the cdk inhibitor p21. Ciz1 and its splice variants have been linked to a number of proliferative disorders, ranging from arthritis to cancer. In addition to actively proliferating cells, Ciz1 foci can also be detected in terminally differentiated cells including adult cardiomyocytes. It is currently unclear whether this retains function or is a remnant of the final round of cardiomyocyte DNA replication leading to the quiescent bi-nucleated state.

In this study we have generated a conditional binary transgenic mouse model that enables us to specifically upregulate expression of Ciz1 in cardiomyocytes. Double transgenic adult hearts are enlarged due to cardiomyocyte hyperplasia but show no other developmental abnormalities. Consistent with this, Millar catheter assessment shows no evidence of cardiac dysfunction. Individual cardiomyocytes isolated from double transgenic hearts exhibit altered nuclear dynamics, with a significant increase in number of mono- and multi-nucleated cells relative to bi-nucleated. In vivo EdU DNA replication assays are being used to investigate degree of cell cycle reactivation in the transgenic hearts, and to what extent reactivation is restricted to a sub-set of the cardiomyocyte population. The results raise the interesting possibility that Ciz1 may represent a novel target for therapeutic application following myocardial injury.

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