Molecular anatomical research for the role of gap junction proteins in cardiac function.

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Among gap junction protein connexins, we focused on the function of connexin43 (Cx43) and connexin45 (Cx45) that are the major connexins in cardiac system. First, we analyzed the early myocardial contraction and the cardiac development using Cx43 and Cx45 deficient mice (Cx43-KO and Cx45-KO). We found intriguing differences of phenotypes between two KO mice. Cx43-KO died just after birth but showed coordinated myocardial contraction and formed endocardial cushion. In contrast, Cx45-KO showed initiation of myocardial contraction and partial coordination of contraction at E.8.25 stage, but died within next 24 hours by the atrioventricular contraction block and by the defect in the formation of endocardial cushion. Second, we made conditional KO mice lacking the Cx45 expression specifically in vascular endothelial cells (Cx45-Tie2) and cardiac myocytes (Cx45-CA) respectively, because Cx45 is mainly expressed in these cells. Cx45-CA was lethal due to an atrioventricular contraction block s … More imilar to Cx45-KO though the endocardial cushion was formed. Furthermore, Cx43/45 double KO showed the same phenotype as Cx45-KO. These data suggest the functions of Cx43 and Cx45 in the initiation of myocardial contraction and the formation of endocardial cushion as following. (1) Cx43 is scarcely involved in these processes. (2) Lacking Cx45 in myocardial cells induces contraction block. (3) Lacking Cx45 both in myocardial cells and endocardial endothelial cells induces defect in the formation of endocardial cushion.In addition to these results, the deficiency in the formation of endocardial cushion varied in Cx45-CA mice, suggesting that soluble factor derived from Cx45 expressing cells in heart is essential for these processes. We proposed the new model ; Activation of Ca^<2+> dependent transcription factor NFATc1, which is involved in valve induction in heart development, is critical for the formation of endocardial cushion. In this model, Ca^<2+> wave propagates by passing through Cx45 containing gap junctions and triggers the synchronized activation of Ca^<2+>/calcineurin/NFATc1 system.Cx45-KO showed moderately coordinated contraction until lethal stage. This suggests another gap junction protein, pannexin that is a vertebrate homologue of innexin for example, might be involved in the formation of the functional gap junction at early stages of cardiac development. This should be addressed afterwards. Less