Complete heart block and sudden death in mice overexpressing calreticulin

The expression of calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired car diac development, knockout of the Calreticulin gene is lethal during embryo genesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression o f calreticulin in the postnatal heart, by producing transgenic mice that ov erexpress the protein in the heart. These transgenic animals exhibit decrea sed systolic function and inward I-Ca,I-L,I- low levels of connexin43 and c onnexin40, sinus bradycardia, and prolonged atrioventricular (AV) node cond uction followed by complete heart block and sudden death. We conclude that postnatal downregulation of calreticulin is essential in the development of the cardiac conductive system, in particular in the sinus and AV nodes, wh en an inward Ca2+ current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardi ac death, which involves high expression of calreticulin in the heart.