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PMID: 15340063 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice.

Molecular and cellular biology ·Vol. 24 ·No. 18 ·2004-09-00 ·Pages 8007-17

Hamada H, Suzuki M, Yuasa S, Mimura N, Shinozuka N, Takada Y, Suzuki M, Nishino T, Nakaya H, Koseki H, Aoe T

Abstract

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 Ca(2+) 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.

MeSH Terms
Animals Calcium Signaling Cardiomyopathy, Dilated/etiology,genetics,metabolism,pathology Endoplasmic Reticulum/metabolism Golgi Apparatus/metabolism Humans Male Mice Mice, Inbred C57BL Mice, Mutant Strains Mice, Transgenic Models, Cardiovascular Myocytes, Cardiac/metabolism,ultrastructure Protein Folding Rats Rats, Sprague-Dawley Receptors, Peptide/genetics,metabolism Recombinant Proteins/genetics,metabolism Sarcoplasmic Reticulum/metabolism,ultrastructure Stress, Mechanical
Chemicals
KDEL receptor Receptors, Peptide Recombinant Proteins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Hamada Hiromichi
Department of Molecular Embryology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba City, Chiba, Japan.
Suzuki Masashi
Yuasa Shigeki
Mimura Naoya
Shinozuka Norihiro
Takada Yuki
Suzuki Misao
Nishino Takashi
Nakaya Haruaki
Koseki Haruhiko
Aoe Tomohiko
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.18.8007-8017.2004
Published
2004-09-00
Pages
8007-17
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC515036
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.18.8007-8017.2004 PMC Full Text View journal details
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