Arrhythmia induced by spatiotemporal overexpression of calreticulin in the heart.
Calreticulin (CRT) is a Ca(2+)-binding protein of the endoplasmic reticulum essential for cardiac development. For further investigation of the functional mechanism of calreticulin, we generated transgenic mice with spatiotemporal overexpression of calreticulin using a cre-loxP system. To elucidate the role of the protein in cardiogenesis, we adopted Nkx2.5-cre mice for heart specific overexpression. The overexpression of calreticulin was associated with arrhythmia, chamber dilation and sudden death, as observed in 6- to 10-week-old mice. Furthermore, transgenic mice displayed marked edema at 7-weeks of age. RT-PCR analysis revealed that the expression of hyperpolerization-activated cyclic nucleotide-gated channel1 (HCN1), an essential component for cardiac pace maker activity, had receded in the heart of transgenic mice. In addition, the protein level of connexin40 (Cx40), connexin43 (Cx43), components of gap junction, and myocyte-enhancer factor (MEF) 2C, a cardiac-specific transcriptional factor, were reduced in the transgenic mice hearts. These findings suggest that calreticulin affects cardiac arrhythmia with disruption of cardiac signaling, such as the HCN family members, and with low levels of Cx40 and Cx43. Overepression of calreticulin also leads to a decreased protein level of MEF2C and this may cause changes in cardiac structure. Our findings support calreticulin being critical for normal heart function and structure. These mice are a useful model for the study of endoplasmic reticulum proteins, such as calreticulin, in various tissues.
Hattori
Kiyoko
K
Department of Pediatrics, Graduate School of Medical Science, Kumamoto University, Japan.
Nakamura
Kimitoshi
K
Hisatomi
Yuichiro
Y
Matsumoto
Shirou
S
Suzuki
Misao
M
Harvey
Richard P
RP
Kurihara
Hiroki
H
Hattori
Shinzaburo
S
Yamamoto
Tetsuro
T
Michalak
Marek
M
Endo
Fumio
F
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D004721:Endoplasmic Reticulum / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D000097003:Gap Junction alpha-5 Protein
D037282:Calreticulin; D018031:Connexin 43; D017630:Connexins; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D015221:Potassium Channels; D000097003:Gap Junction alpha-5 Protein; C578666:Hcn1 protein, mouse