Hypoxic Induction of Receptor Activity-modifying Protein 2 Alters Regulation of Pulmonary Endothelin-1 by Adrenomedullin: Induction Under Normoxia Versus Inhibition Under Hypoxia.
From: Department of Cardiology and Angiology, University Medical Centre Charité, Campus Mitte, Schumannstr. 20/21, 10117 Berlin, Germany. thomas.dschietzig@charite.de
The Journal of pharmacology and experimental therapeutics
- Publish Date: Apr 2007
- ISSN: 0022-3565
- Volume: 321
- Issue: 1
- Pages: 409-19
- Medium: Print
- Language: English
- Citation (JAMA): Dschietzig Thomas, Richter Christoph, Asswad Louay, et al. Hypoxic Induction of Receptor Activity-modifying Protein 2 Alters Regulation of Pulmonary Endothelin-1 by Adrenomedullin: Induction Under Normoxia Versus Inhibition Under Hypoxia.. J. Pharmacol. Exp. Ther. Apr 2007;321:409-19
Abstract
The vasodilator adrenomedullin (AM) is up-regulated in pulmonary hypertension, and inhaled AM is beneficial in patients. Therefore, we investigated the effects of AM on pulmonary endothelin-1 (ET-1). In normoxic isolated rat lungs (IRL) and rat pulmonary artery endothelial cells (RPAEC), the calcitonin gene-related peptide type-1 receptor (CGRP1R) antagonist human (h)CGRP(8-37) decreased ET-1 secretion, and the AM receptor antagonist hAM(22-52) had no effect. Exogenous AM (1 and 10 pM) increased ET-1 levels, which was abolished by hCGRP(8-37) and protein kinase A (PKA) inhibition. At 50 and 100 pM, AM decreased ET-1, an effect sensitive to hAM(22-52), NO inhibition, and protein kinase G (PKG) inhibition. In RPAEC, these results were attributed to altered ET-1 gene expression; low exogenous AM also promoted activity of endothelin-converting enzyme, and high AM increased the number of endothelin type-B (ETB) receptor sites. Hypoxia significantly elevated AM and ET-1 levels in IRL and RPAEC, and hAM(22-52), NO inhibition, or PKG inhibitors caused a further ET-1 rise. These interventions also prevented the hypoxia-related increase in ETB sites in RPAEC. In RPAEC, both high AM and hypoxia down-regulated receptor activity-modifying protein (RAMP)1, but they up-regulated RAMP2 protein and AM receptor sites, and RAMP2 silencing by small interference RNA proved its pivotal role for signal switching. In conclusion, endogenous pulmonary AM up-regulates ET-1 and endothelin-converting enzyme activity under physiological conditions, via CGRP1R and PKA. In contrast, hypoxia-induced high AM levels, via AM1 receptor and NO/PKG, down-regulate ET-1 gene expression and promote expression of ETB receptors. This hypoxia-related switch of AM signaling can be attributed to up-regulation of the RAMP2/AM1 receptor system.
Mesh Headings (Keywords): Adrenomedullin, Animals, Anoxia, Anti-Inflammatory Agents, Non-Steroidal, Blotting, Western, Calcitonin Gene-Related Peptide, Cyclic AMP, Cyclic GMP, Endothelial Cells, Endothelin-1, Intracellular Signaling Peptides and Proteins, Lung, Male, Membrane Proteins, Nitric Oxide, RNA, Messenger, RNA, Small Interfering, Rats, Rats, Wistar, Receptor, Endothelin B, Signal Transduction, Solvents
Check for Full Text / PubMed Unique Identifier (PMID): 17251392
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