Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes.
Long-standing diabetes causes cardiovascular complications including direct cardiac muscle weakening known as diabetic cardiomyopathy. This is characterized by disturbances in both cardiac contraction and relaxation, which are maintained by calcium homeostasis in cardiac cells. Our recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vasculopathy through their engagement of the receptor for AGE (RAGE). Here we show that AGE and RAGE may directly affect the myocardial Ca(2+) homeostasis. We created transgenic mice that overexpressed human RAGE in the heart and analyzed the Ca(2+) transients in cultivated cardiac myocytes (CM) from the RAGE-transgenic and non-transgenic control fetuses. RAGE overexpression was found to reduce the systolic and diastolic intracellular calcium concentration ([Ca(2+)](i)). Exposure to AGE caused a significant prolongation of the decay time of [Ca(2+)](i) in CM from control mice, and this response was augmented in CM from the RAGE transgenic mice. The results suggest that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.
Petrova
Ralica
R
Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
Yamamoto
Yasuhiko
Y
Muraki
Katsuhiko
K
Yonekura
Hideto
H
Sakurai
Shigeru
S
Watanabe
Takuo
T
Li
Hui
H
Takeuchi
Masayoshi
M
Makita
Zenji
Z
Kato
Ichiro
I
Takasawa
Shin
S
Okamoto
Hiroshi
H
Imaizumi
Yuji
Y
Yamamoto
Hiroshi
H
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium