Two Distinct Mechanisms of Angiotensin II-Induced Negative Regulation of the Mitogen-Activated Protein Kinases in Cultured Cardiac Myocytes.
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- HIROI Yukio
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine
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- HIROI Junko
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine
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- KUDOH Sumiyo
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine
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- YAZAKI Yoshio
- International Medical Center of Japan
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- NAGAI Ryozo
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine
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- KOMURO Issei
- Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine
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Increasing evidence has suggested that mitogen-activated protein kinases (MAPKs) play important roles in the development of cardiac hypertrophy. We and others have reported that the activity of MAPKs is tightly regulated by angiotensin II (Ang II) in cardiac myocytes. In the present study, we determined the molecular mechanism of Ang II-induced inactivation of MAPKs in rat neonatal cardiac myocytes. Ang II increased MAPK phosphatase 1 (MKP-1) gene expressions within 10 min. Levels of MKP-1 transcripts peaked at 30 min and gradually decreased thereafter. The increase in MKP-1 mRNA levels was Ang II-concentration dependent. An Ang II type 1 receptor (AT1)-specific antagonist, CV-11974, completely suppressed the Ang II-induced increase in MKP-1 gene expression, while a type 2 receptor (AT2)-specific antagonist, PD-123319, had no significant effects. Induction of MKP-1 gene expressions by Ang II was inhibited by pretreatment with an intracellular Ca2+ chelator, BAPTA-AM, or with the protein kinase C inhibitors, H-7 and Calphostin C. Phorbol ester and Ca2+ ionophore both significantly increased MKP-1 mRNA levels and showed synergistic action. Overexpression of MKP-1 cDNA blocked the Ang II-induced increase in expressions of immediate early response genes. In addition, Ang II-induced MAPK activation was significantly inhibited by pretreatment with CV-11974, but significantly enhanced by pretreatment with PD-123319. Addition of the AT2 agonist, CGP42112A, reduced basal MAPK activities, and pretreatment with PD-123319 abolished MAPK inactivation by CGP42112A. In conclusion, these observations suggest that Ang II negatively regulates MAPKsthrough AT1 receptors by increasing MKP-1 mRNA levels and through AT2 receptors by unknown mechanisms. (Hypertens Res 2001; 24: 385-394)
収録刊行物
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- Hypertension Research
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Hypertension Research 24 (4), 385-394, 2001
日本高血圧学会
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詳細情報 詳細情報について
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- CRID
- 1390001204719817216
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- NII論文ID
- 10009564311
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- NII書誌ID
- AA10847079
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- COI
- 1:CAS:528:DC%2BD3MXmslWns74%3D
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- ISSN
- 13484214
- 09169636
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- PubMed
- 11510751
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可