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J Clin Invest. 2001 May;107(10):1245-53.

Complete heart block and sudden death in mice overexpressing calreticulin.

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1
Canadian Institutes of Health Research Group in Molecular Biology of Membrane Proteins and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

Abstract

The expression of calreticulin, a Ca(2+)-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired cardiac development, knockout of the Calreticulin gene is lethal during embryogenesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression of calreticulin in the postnatal heart, by producing transgenic mice that overexpress the protein in the heart. These transgenic animals exhibit decreased systolic function and inward I(Ca,L), low levels of connexin43 and connexin40, sinus bradycardia, and prolonged atrioventricular (AV) node conduction 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, when an inward Ca(2+) current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardiac death, which involves high expression of calreticulin in the heart.

Comment in

PMID:
11375414
PMCID:
PMC209301
DOI:
10.1172/JCI12412
[Indexed for MEDLINE]
Free PMC Article
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