Coordinate regulation of endothelin and adrenomedullin secretion by oxidative stress in endothelial cells

Takatoshi Saito, Hiroshi Itoh, Tae Hwa Chun, Yasutomo Fukunaga, Jun Yamashita, Kentaro Doi, Tokuji Tanaka, Mayumi Inoue, Ken Masatsugu, Naoki Sawada, Satsuki Sakaguchi, Hiroshi Arai, Masashi Mukoyama, Katsuyoshi Tojo, Tatsuo Hosoya, Kazuwa Nakao

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

To elucidate the significance of oxidative stress in the modulation of endothelial functions, we examined the effects of H2O2 on the expression of two endothelium-derived vasoactive peptides, endothelin (ET) and adrenomedullin (Am), and their interaction. H2O2 dose 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 H2O2 reductase, 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, H2O2 increased 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. H2O2 increased 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+]i under 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume281
Issue number3 50-3
Publication statusPublished - 2001
Externally publishedYes

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Adrenomedullin
Endothelins
Oxidative Stress
Endothelial Cells
Endothelin-1
Messenger RNA
8-Bromo Cyclic Adenosine Monophosphate
Ionomycin
Thapsigargin
Tocopherols
Ionophores
Colforsin
Vitamin E
Vascular Diseases
Endoplasmic Reticulum
Catalase
Oxidation-Reduction
Endothelium
Blood Vessels
Adenosine Triphosphatases

Keywords

  • C-type natriuretic peptide
  • cAMP
  • Hydrogen peroxide
  • Intracellular Ca
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Coordinate regulation of endothelin and adrenomedullin secretion by oxidative stress in endothelial cells. / Saito, Takatoshi; Itoh, Hiroshi; Chun, Tae Hwa; Fukunaga, Yasutomo; Yamashita, Jun; Doi, Kentaro; Tanaka, Tokuji; Inoue, Mayumi; Masatsugu, Ken; Sawada, Naoki; Sakaguchi, Satsuki; Arai, Hiroshi; Mukoyama, Masashi; Tojo, Katsuyoshi; Hosoya, Tatsuo; Nakao, Kazuwa.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 281, No. 3 50-3, 2001.

Research output: Contribution to journalArticle

Saito, T, Itoh, H, Chun, TH, Fukunaga, Y, Yamashita, J, Doi, K, Tanaka, T, Inoue, M, Masatsugu, K, Sawada, N, Sakaguchi, S, Arai, H, Mukoyama, M, Tojo, K, Hosoya, T & Nakao, K 2001, 'Coordinate regulation of endothelin and adrenomedullin secretion by oxidative stress in endothelial cells', American Journal of Physiology - Heart and Circulatory Physiology, vol. 281, no. 3 50-3.
Saito, Takatoshi ; Itoh, Hiroshi ; Chun, Tae Hwa ; Fukunaga, Yasutomo ; Yamashita, Jun ; Doi, Kentaro ; Tanaka, Tokuji ; Inoue, Mayumi ; Masatsugu, Ken ; Sawada, Naoki ; Sakaguchi, Satsuki ; Arai, Hiroshi ; Mukoyama, Masashi ; Tojo, Katsuyoshi ; Hosoya, Tatsuo ; Nakao, Kazuwa. / Coordinate regulation of endothelin and adrenomedullin secretion by oxidative stress in endothelial cells. In: American Journal of Physiology - Heart and Circulatory Physiology. 2001 ; Vol. 281, No. 3 50-3.
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AU - Saito, Takatoshi

AU - Itoh, Hiroshi

AU - Chun, Tae Hwa

AU - Fukunaga, Yasutomo

AU - Yamashita, Jun

AU - Doi, Kentaro

AU - Tanaka, Tokuji

AU - Inoue, Mayumi

AU - Masatsugu, Ken

AU - Sawada, Naoki

AU - Sakaguchi, Satsuki

AU - Arai, Hiroshi

AU - Mukoyama, Masashi

AU - Tojo, Katsuyoshi

AU - Hosoya, Tatsuo

AU - Nakao, Kazuwa

PY - 2001

Y1 - 2001

N2 - To elucidate the significance of oxidative stress in the modulation of endothelial functions, we examined the effects of H2O2 on the expression of two endothelium-derived vasoactive peptides, endothelin (ET) and adrenomedullin (Am), and their interaction. H2O2 dose 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 H2O2 reductase, 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, H2O2 increased 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. H2O2 increased 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+]i under 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.

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KW - cAMP

KW - Hydrogen peroxide

KW - Intracellular Ca

KW - Nitric oxide

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