Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice.
Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (alphaCGRP and betaCGRP), and the main CGRP receptors are probably composed of a calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein (RAMP)1. However, the physiological functions of CGRP that are mediated through the CLR/RAMP1 receptors remain to be clarified. For an improved understanding of the functions, we generated mice deficient in RAMP1, a specific subunit of CGRP receptors, by a conditional gene-targeting technique. The RAMP1-deficient mice (RAMP1(-/-)) exhibited high blood pressure, with no changes in heart rate. alphaCGRP was found to have a potent vascular relaxant activity compared with betaCGRP in the artery of the WT (RAMP1(+/+)) mice. The activities of both CGRP isoforms were remarkably suppressed in the arteries of the RAMP1(-/-) mice. The LPS-induced inflammatory responses of the RAMP1(-/-) mice revealed a transient and significant increase in the serum CGRP levels and high serum levels of proinflammatory cytokines compared with the RAMP1(+/+) mice. alphaCGRP and betaCGRP equally suppressed the production of TNF-alpha and IL-12 in bone marrow-derived dendritic cells stimulated with lipopolysaccharide. Their inhibitory effects were not observed in the bone marrow-derived dendritic cells of the RAMP1(-/-) mice. These results indicate that CGRP signaling through CLR/RAMP1 receptors plays a crucial role in the regulation of both blood pressure by vascular relaxation and proinflammatory cytokine production from dendritic cells.
Tsujikawa
Kazutake
K
Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan. tujikawa@phs.osaka-u.ac.jp
Yayama
Katsutoshi
K
Hayashi
Tamon
T
Matsushita
Hiroaki
H
Yamaguchi
Taijiro
T
Shigeno
Tomomi
T
Ogitani
Yusuke
Y
Hirayama
Megumi
M
Kato
Tetsuya
T
Fukada
So-ichiro
S
Takatori
Shingo
S
Kawasaki
Hiromu
H
Okamoto
Hiroshi
H
Ikawa
Masahito
M
Okabe
Masaru
M
Yamamoto
Hiroshi
H
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001853:Bone Marrow / Q000276:immunology; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D006973:Hypertension / Q000235:genetics*; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000235:genetics
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide