Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-ATPase 2 gene transcription through modification of Sp1 binding.
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.
Koitabashi
Norimichi
N
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Arai
Masashi
M
Tomaru
Koichi
K
Takizawa
Takako
T
Watanabe
Atai
A
Niwano
Kazuo
K
Yokoyama
Tomoyuki
T
Wuytack
Frank
F
Periasamy
Muthu
M
Nagai
Ryozo
R
Kurabayashi
Masahiko
M
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016329:Sp1 Transcription Factor / Q000378:metabolism*
C506948:Atp2a2 protein, rat; D002227:Carbazoles; D011412:Propanolamines; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; D000077261:Carvedilol; D006861:Hydrogen Peroxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases