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Molecular and Cellular Biology, September 2004, p. 8007-8017, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8007-8017.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice

Department of Molecular Embryology,¹ Department of Pharmacology,² Department of Anesthesiology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba City, Chiba,⁴ Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo,³ Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama,⁵ Center for Animal Resources and Development, Kumamoto University, Kumamoto City, Kumamoto, Japan⁶

Received 19 February 2004/ Returned for modification 29 March 2004/ Accepted 25 June 2004

Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca²⁺ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.

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