Title: Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-ATPase 2 gene transcription through modification of Sp1 binding
Authors: Koitabashi, Norimichi ×
Arai, Masashi
Tomaru, Koichi
Takizawa, Takako
Watanabe, Atai
Niwano, Kazuo
Yokoyama, Tomoyuki
Wuytack, Frank
Periasamy, Muthu
Nagai, Ryozo
Kurabayashi, Masahiko #
Issue Date: Mar-2005
Publisher: Academic Press
Series Title: Biochemical and Biophysical Research Communications vol:328 issue:1 pages:116-124
Abstract: Carvedilol is a beta-adrenoceptor blocker and a potent antioxidant that improves cardiac function in patients with heart failure. The restoration of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression may be an underlying mechanism of its beneficial effects on cardiac function. In primary cultured neonatal rat cardiac myocytes, treatment with either carvedilol or its beta-receptor inactive metabolite, BM910228, attenuated the hydrogen peroxide-mediated decrease in SERCA2 mRNA and protein levels, while metoprolol, a pure beta-blocker, had no effect. Moreover, carvedilol itself significantly enhanced SERCA2 gene transcription, suggesting that carvedilol specifically restores SERCA2 gene transcription. Site-directed mutagenesis revealed that two Sp1 sites in the SERCA2 gene promoter region mediated the response to carvedilol under oxidative stress. Further, electrophoretic mobility shift assays revealed that Sp1 and Sp3 transcription factors correlated with carvedilol-mediated changes in the promoter assays. These studies may provide a mechanistic explanation for the beneficial effects of carvedilol in heart failure.
ISSN: 0006-291X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Physiology Section (-)
Laboratory of Cellular Transport Systems
× corresponding author
# (joint) last author

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