Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10770958 | Biochemical and Biophysical Research Communications | 2005 | 9 Pages |
Abstract
Carvedilol is a β-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 β-receptor inactive metabolite, BM910228, attenuated the hydrogen peroxide-mediated decrease in SERCA2 mRNA and protein levels, while metoprolol, a pure β-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.
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Authors
Norimichi Koitabashi, Masashi Arai, Koichi Tomaru, Takako Takizawa, Atai Watanabe, Kazuo Niwano, Tomoyuki Yokoyama, Frank Wuytack, Muthu Periasamy, Ryozo Nagai, Masahiko Kurabayashi,