1. Coordinate regulation of endothelin and adrenomedullin secretion by oxidative stress in endothelial cells
- Author
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Mayumi Inoue, Masashi Mukoyama, Naoki Sawada, Yasutomo Fukunaga, Hiroshi Itoh, Tokuji Tanaka, Jun K. Yamashita, Katsuyoshi Tojo, Takatoshi Saito, Tatsuo Hosoya, Ken Masatsugu, Satsuki Sakaguchi, Kentaro Doi, Kazuwa Nakao, Tae Hwa Chun, and Hiroshi Arai
- Subjects
medicine.hormone ,medicine.medical_specialty ,Physiology ,Biology ,medicine.disease_cause ,Antioxidants ,Nitric oxide ,Endothelins ,Adrenomedullin ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Cyclic AMP ,medicine ,Animals ,Secretion ,RNA, Messenger ,Enzyme Inhibitors ,Cyclic GMP ,Cells, Cultured ,Dose-Response Relationship, Drug ,Endothelin-1 ,Ionophores ,Colforsin ,Antibodies, Monoclonal ,Hydrogen Peroxide ,Oxidants ,Endothelin 1 ,Endothelial stem cell ,Oxidative Stress ,Carotid Arteries ,Endocrinology ,chemistry ,Calcium ,Cattle ,Endothelium, Vascular ,Peptides ,Cardiology and Cardiovascular Medicine ,Endothelin receptor ,Oxidative stress - Abstract
To elucidate the significance of oxidative stress in the modulation of endothelial functions, we examined the effects of H2O2on the expression of two endothelium-derived vasoactive peptides, endothelin (ET) and adrenomedullin (Am), and their interaction. H2O2dose dependently suppressed ET secretion and ET-1 mRNA expression in bovine carotid endothelial cells (ECs). Menadion sodium bisulfate, a redox cycling drug, also decreased ET secretion in a dose-dependent manner. Catalase, a H2O2reductase, and dl-α-tocopherol (vitamin E) significantly inhibited H2O2-induced suppression of ET secretion. Downregulation of ET-1 mRNA under oxidative stress was regulated at the transcriptional level. In contrast, H2O2increased Am secretion (and its mRNA expression) accompanied by the augmentation of cAMP production. Am, as well as 8-bromo-cAMP and forskolin decreased ET secretion in a dose-dependent fashion. Furthermore, an anti-Am monoclonal antibody that we developed abolished H2O2-induced suppression of ET secretion at 6–24 h after the addition of H2O2. H2O2increased the intracellular Ca2+concentration ([Ca2+]i). Moreover, treatment with ionomycin, a Ca2+ionophore, and thapsigargin, an inhibitor of endoplasmic reticulum ATPase, decreased ET secretion dose dependently for 3 h. These results suggest that the production of ET was decreased via activation of the Am-cAMP pathway and by the elevation of [Ca2+]iunder oxidative stress. These findings elucidate the coordinate expression of two local vascular hormones, ET and Am, under oxidative stress, which may protect against vascular diseases.
- Published
- 2001