論文 - 北村 和雄
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Regulation of production and secretion of adrenomedullin in the cardiovascular system 査読あり
Eto T., Kato J., Kitamura K.
Regulatory Peptides 112 ( 1-3 ) 61 - 69 2003年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Regulatory Peptides
Adrenomedullin (AM) has multi-functional properties, of which the vasodilatory hypotensive effect is the most characteristic. AM and its gene are ubiquitous in a variety of tissues and organs, in the cardiovascular system, as well as the adrenal medulla. AM secretion, especially in cardiovascular tissues, is regulated mainly by mechanical stressors such as shear stress, inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF), and lipopolysaccharide (LPS), hormones such as angiotensin (Ang) II and endothelin (ET)-1, and metabolic factors such as hypoxia, ischemia, or hyperglycemia. Elevation of plasma AM due to overproduction in response to one or more of these stimuli in pathological conditions may explain the raised plasma AM levels present in cardiovascular and renal diseases such as congestive heart failure, myocardial infarction, hypertension, chronic renal failure, stroke, diabetes mellitus, and septic shock. In addition to shear stress, stretching of cardiomyocytes may be another mechanical stimulus for AM synthesis and secretion. Our recent studies have shown the importance of aldosterone and additional hormonal factor on AM secretion in vascular wall. © 2003 Published by Elsevier Science B.V.
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Expression of adrenomedullin and its receptor by chondrocyte phenotype cells 査読あり
Chosa E., Hamada H., Kitamura K., Kuwasako K., Yanagita T., Eto T., Tajima N.
Biochemical and Biophysical Research Communications 303 ( 1 ) 379 - 386 2003年3月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
For clarifying a process of de-differentiation in culturing chondrocytes, the present study was undertaken to investigate the secretion of adrenomedullin (AM) by chondrocyte phenotype cells and whether or not AM effects this proliferation in a cAMP-dependent fashion. Chondrocyte phenotype cells expressed AM and the AM receptor, and secreted high concentration of AM into the culture medium. When added to cultures, AM increased the intracellular cAMP level and decreased the number of these cells in a similar concentration-dependent fashion. Addition of forskolin and dibutyryl-cAMP caused a significant decrease in the number of these cells. Furthermore, the effect of AM was inhibited by a cAMP-dependent protein kinase A inhibitor (H89). The present findings indicate that AM has an autocrine/paracrine type of anti-proliferative effect on these cells mediated via a cAMP-dependent pathway and raise the possibility that AM plays a role in the local modulation of a process of de-differentiation by culturing chondrocyte phenotype cells. © 2003 Elsevier Science (USA). All rights reserved.
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Kuwasako K., Kitamura K., Nagoshi Y., Eto T.
Biochemical and Biophysical Research Communications 301 ( 2 ) 460 - 464 2003年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
We tested whether heterodimers comprised of calcitonin (CT) receptor lacking the 16-amino acid insert in intracellular domain 1 (CTRI1-) and receptor activity-modifying protein (RAMP) can function not only as calcitonin gene-related peptide (CGRP) receptors but also as adrenomedullin (AM) receptors. Whether transfected alone or together with RAMP, human (h)CTRI1- appeared mainly at the surface of HEK-293 cells. Expression of CTRI1- alone led to significant increases in cAMP in response to hCGRP or hAM, though both peptides remained about 100-fold less potent than hCT. However, the apparent potency of AM, like that of CGRP, approached that of CT when CTRI1- was co-expressed with RAMP. CGRP- or AM-evoked cAMP production was strongly inhibited by salmon CT-(8-32), a selective amylin receptor antagonist, but not by hCGRP-(8-37) or hAM-(22-52), antagonists of CGRP and AM receptors, respectively. Moreover, the inhibitory effects of CT-(8-32) were much stronger in cells co-expressing CTRI1- and RAMP than in cells expressing CTRI1- alone. Co-expression of CTRI1- with RAMP thus appears to produce functional CT-(8-32)-sensitive AM receptors. © 2003 Elsevier Science (USA). All rights reserved.
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Yamaga J., Hashida S., Kitamura K., Tokashiki M., Aoki T., Inatsu H., Ishikawa N., Kangawa K., Morishita K., Eto T.
Hypertension Research 26 ( SUPPL. ) S45 - S53 2003年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
The mature form of the vasodilator peptide adrenomedullin (AM-m) is synthesized from a glycine-extended precursor (AM-Gly) by enzymatic amidation. We have developed a highly sensitive enzyme immunoassay (Immune Complex Transfer Enzyme Immunoassay; ICTEIA) that enables us to measure levels of AM-Gly in plasma and tissue directly. The detection limit of this assay is 1 amol/assay, and the intra- and inter-assay precision are 4.5-14.1% and 9.9-20.5%, respectively. Dilution curves for plasma samples showed good linearity, and the analytical recovery was 107-116.6%. Using ICTEIA, we determined that the plasma concentration of immunoreactive AM-Gly is substantially higher than that of AM-m (5.22±2.56 vs. 1.21± 0.79 fmol/ml). In contrast, levels of AM-Gly were much lower than those of AM-m in the lung, heart, kidney, adrenal gland and liver. We also evaluated AM-Gly and AM-m levels in rats in a morbid state induced by intraperitoneal administration of lipopolysaccharide (LPS). In most tissues, levels of AM-m and AM-Gly were both increased by LPS; however, AM-Gly/AM-m ratios were not significantly affected, which suggests that AM-Gly is rapidly converted to AM-m in tissue.
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Adrenomedullin: A possible autocrine or paracrine hormone in the cardiac ventricles 査読あり
Kato J., Tsuruda T., Kitamura K., Eto T.
Hypertension Research 26 ( SUPPL. ) S113 - S119 2003年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
Adrenomedullin (AM), a potent vasodilator peptide originally isolated from pheochromocytoma, is expressed in cardiovascular tissues such as those of the cardiac atria and ventricles. Cell culture experiments have shown that AM peptide is synthesized and secreted from cardiac myocytes and fibroblasts of neonatal rats. Humoral factors, such as angiotensin II (Ang II) and endothelin-1 (ET-1), and mechanical stress due to pressure and volume overload to the heart have been shown to be involved in AM expression of the myocardium in both in vitro and in vivo studies. The effects of AM on cardiomyocytes and cardiac fibroblasts have been examined in in vitro studies, with the result that AM was shown to exert inhibitory actions on myocyte hypertrophy and on proliferation and collagen production of cardiac fibroblasts in an autocrine or paracrine manner. In rats, experimental therapeutic intervention consisting of transfer of the AM gene or of recombinant AM appears to partly inhibit the progression of cardiac hypertrophy and remodeling. It has been shown that the calcitonin receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) act together to function as AM receptors, although in this regard there are a number of issues, including the cellular mechanism of AM actions, that remain to be addressed. In addition, the role of proadrenomedullin N-terminal 20 peptide (PAMP), which is derived from preproAM, is another topic for future experiments. Collectively, the research data accumulating in this area suggest that AM plays a role as an autocrine or paracrine hormone in the cardiac ventricles, and that AM might be utilized as a therapeutic tool in the treatment of hypertensive or ischemic heart disease.
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The function of extracellular cysteines in the human adrenomedullin receptor 査読あり
Kuwasako K., Kitamura K., Uemura T., Nagoshi Y., Kato J., Eto T.
Hypertension Research 26 ( SUPPL. ) S25 - S31 2003年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
When co-expressed with receptor activity-modifying protein (RAMP) 2, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2). In the present study, we examined the function of the cysteine (C) residues in the extracellular loops of human (h)CRLR (C212, C225 and C282) and in the extracellular domain of hRAMP2 (C68, C84, C99 and C131). Using site-directed mutagenesis, the cysteine residues were substituted, one at a time, with alanine (A). Co-expression in HEK293 cells of hRAMP2 with the hCRLR C212A or C282A mutant significantly reduced the 50% of effective concentration (EC50) for AM-evoked cyclic adenosine monophosphate (cAMP) production, despite full cell surface expression of the receptor heterodimer. Co-expression of the C225A mutant had no effect on [125I]AM binding or receptor signaling. These results suggest that the cysteine residues in the first (C212) and the second (C282) extracellular loops form a disulfide bond that is important for stabilizing the receptor in the correct conformation for ligand binding and activation. Cells expressing hCRLR with an hRAMP2 mutant (C68A, C84A, C99A or C131A) showed no specific AM binding or AM-stimulated cAMP accumulation. Though abundant in the intracellular compartment, these receptors were not detected at the cell surface, suggesting that all four cysteine residues are essential for efficient transport to the plasma membrane. Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer.
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Tokura T., Kinoshita H., Fujimoto S., Kitamura K., Eto T.
Nephron. Clinical practice 95 ( 2 ) 47 - 54 2003年
掲載種別：研究論文（学術雑誌） 出版者・発行元：Nephron. Clinical practice
BACKGROUND: Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. However, the profile of PAMP in hemodialyzed (HD) patients has not been determined. METHODS: We measured plasma levels of PAMP, total AM (tAM) and a mature form of AM (mAM, the biologically active form) in HD patients (n = 31) and in normal controls (n = 21). RESULTS: Plasma concentrations of PAMP before HD were significantly higher than those in controls (4.02 +/- 0.24 vs. 1.64 +/- 0.12 fmol/ml, p < 0.001) and decreased to the control level after HD (2.17 +/- 0.18 vs. 1.64 +/- 0.12 fmol/ml; NS). The plasma PAMP level before HD significantly correlated with weight gain during HD sessions (r = 0.41, p < 0.05), but not with predialysis blood pressure. The concentrations of mAM before and after HD were significantly higher than those in controls. The plasma mAM level before HD significantly correlated with weight gain during HD sessions, but not with predialysis blood pressure. The plasma level of PAMP did not correlate with that of mAM in HD patients. CONCLUSION: PAMP and AM may be involved in the regulation of blood volume in patients undergoing HD. Copyright 2003 S. Karger AG, Basel
DOI： 10.1159/000073670
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Increased adrenomedullin concentration in cerebrospinal fluid in patients with septic shock 査読あり
Naoto Nagata 1, Johji Kato, Kazuo Kitamura, Mari Kawamoto, Hirosi Katsuki, Masaharu Yamaga, Tanenao Eto, Shingo Tateyama, Mayumi Takasaki
J Med 34 ( 1-6 ) 59 - 66 2003年
掲載種別：研究論文（学術雑誌）
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受容体活性調節蛋白(RAMP)とカルシトニン受容体(CTR)で形成されるカルシトニン遺伝子関連ペプチド(CGRP)受容体の薬理学的特徴 査読あり
桑迫健二、名越康子、曹遠寧、鶴田敏博、北村和雄、江藤胤尚
日本内分泌学会雑誌 79 ( 2 ) 542 - 542 2003年
掲載種別：研究論文（学術雑誌）
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ヒトにおけるアドレノメデュリンの心機能改善効果の検討 査読あり
鈴木良彦、北俊弘、北村和雄、江藤胤尚、
日本内分泌学会雑誌 79 ( 2 ) 523 - 523 2003年
掲載種別：研究論文（学術雑誌）
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心筋梗塞(MI)急性期のアドレノメデュリン(AM)投与は慢性期の心機能低下を抑制する 査読あり
中村
日本内分泌学会雑誌 79 ( 2 ) 523 - 523 2003年
掲載種別：研究論文（学術雑誌）
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Nakamura R., Kato J., Kitamura K., Onitsuka H., Imamura T., Marutsuka K., Asada Y., Kangawa K., Eto T.
Cardiovascular Research 56 ( 3 ) 373 - 380 2002年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Cardiovascular Research
Objective: We previously reported that plasma adrenomedullin (AM) levels increase in patients with acute myocardial infarction (MI) and AM inhibits growth of rat cardiac myocytes and fibroblasts. The aim of this study was to examine the effects of long-term administration of AM on left ventricular (LV) remodeling, hemodynamic and hormonal parameters in a rat model of MI. Methods: Rats with MI induced by left coronary ligation were intravenously infused with 1.0 μg/h of recombinant human AM or saline by osmotic mini-pump. After infusion for 4 weeks, hemodynamic and hormonal studies were performed, and the myocyte size and collagen volume in non-infarct LV area were quantified morphometrically. Results: When compared with the MI rats infused with saline, continuous infusion of AM reduced the heart weight/body weight (4.4±0.2 vs. 3.6±0.1 g/kg, P<0.01), myocyte size (922±23 vs. 868±10 μm2, P<0.05) and collagen volume fraction of non-infarct LV area (7.6±0.8 vs. 4.8±0.5%, P<0.05), without affecting the infarct size. The AM infusion had no significant effect on the arterial pressure, but decreased the LV end-diastolic pressure (8.8±1.8 vs. 4.4±0.5 mmHg, P<0.05) in the MI rats. The plasma level of endogenous rat AM in the MI rats infused with human AM was reduced by 27% (P<0.05), with a slight reduction of plasma atrial natriuretic peptide, compared with the control. Conclusions: Continuous administration of AM had beneficial effects on LV remodeling and hemodynamics in MI rats, suggesting the possibility that this peptide could be a useful therapeutic tool for acute MI. © 2002 Elsevier Science B.V. All rights reserved.
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Hamada H., Kitamura K., Chosa E., Eto T., Tajima N.
Peptides 23 ( 12 ) 2163 - 2168 2002年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Peptides
Adrenomedullin (AM) is a 52 amino acid peptide that is synthesized in a variety of tissues, including the vessels and bones. This study showed that normal human osteoblast (NHOst) secreted immunoreactive AM and that AM stimulated intracellular cAMP production in these cells. An anti-AM monoclonal antibody, which inhibited endogenous AM, caused the number of NHOst to decrease. The effect of a low concentration AM was inhibited by addition of a cAMP-dependent protein kinase A inhibitor (H89). These data suggest that AM is an autocrine or paracrine regulator that promotes the proliferation of NHOst via the cAMP pathway. © 2002 Elsevier Science Inc. All rights reserved.
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Mitsuda Y., Takimoto A., Kamitani S., Kitamura K., Sakata T., Mitsushima K.
Protein Expression and Purification 25 ( 3 ) 448 - 455 2002年11月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Protein Expression and Purification
Human adrenomedullin (hAM) is a 52-amino-acid regulatory peptide containing a six-membered ring structure and an amidated C-terminus, features that are essential for its biological activity. Here, we describe a simple and effective protocol for producing large quantities of highly pure, functional recombinant hAM. A peptide precursor (hAM-Gly) was expressed in Escherichia coli as a fusion protein with thioredoxin and collected as inclusion bodies. The fusion protein was then digested with BLase, a glutamate-specific endopeptidase, to prepare hAM-Gly. The essential ring structure formed spontaneously, while the terminal amide was generated by conversion of the added glycine residue using peptidylglycine α-amidating enzyme. The low solubility of hAM-Gly enabled the use of a selective precipitation/extraction method to generate a product that was 80-90% pure, which was sufficient to proceed with the α-amidating enzyme reaction. The resultant hAM was then purified further by column chromatography. The final yield was about 82 mg/L of bacterial culture, and the purity, determined by reverse phase HPLC, was >99:5%. The recombinant hAM was biologically active, eliciting concentration-dependent increases in cAMP in CHO-K1 cells expressing a specific hAM receptor and hypotensive responses when intravenously injected into rats. This new approach to the synthesis of hAM is simpler and more cost-effective for large-scale production than chemical synthesis. It therefore represents a new powerful tool that has the potential to facilitate analysis of the structure and function of hAM, as well as the development of new therapeutic protocols for the treatment of ailments such as hypertension. © 2002 Elsevier Science (USA). All rights reserved.
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Kato J., Kitamura K., Uemura T., Kuwasako K., Kita T., Kangawa K., Eto T.
Hypertension Research 25 ( 6 ) 887 - 892 2002年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert vasodilator and natriuretic actions and are thought to share roles in counteracting the progression of hypertension or heart failure as circulating or locally-acting hormones. However, little data is available with regard to their roles in subjects who have no apparent cardiovascular diseases. The present study was carried out to identify the factors that affect plasma levels of AM, ANP and BNP in the general population. We measured the plasma levels of AM, ANP and BNP in 184 local residents who had a scheduled regular health checkup, and compared the findings with those for other clinical parameters. Univariate analyses showed that the plasma levels of AM, ANP and BNP were significantly correlated with age. The plasma levels of ANP and BNP were also significantly correlated with systolic blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness of the great vessels. Multivariate analyses conducted using a stepwise method revealed that age was a significant, independent variable for the plasma levels of AM, ANP and BNP. In addition, PP was a significant factor for the plasma levels of ANP and BNP, while the plasma AM was significantly associated with body mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANP and BNP increased in association with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system.
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Nagoshi Y., Kuwasako K., Ito K., Uemura T., Kato J., Kitamura K., Eto T.
European Journal of Pharmacology 450 ( 3 ) 237 - 243 2002年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：European Journal of Pharmacology
The receptor activity-modifying protein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8-37), but not the adrenomedullin receptor antagonist adrenomedullin-(22-52), blocked the adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to adrenomedullin; in this case, the effect was blocked by adrenomedullin-(22-52) but not by α-CGRP-(8-37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of adrenomedullin are potently antagonized by α-CGRP-(8-37). © 2002 Elsevier Science B.V. All rights reserved.
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Ishiyama Y., Kitamura K., Eto T.
Biochemical and Biophysical Research Communications 293 ( 2 ) 741 - 746 2002年7月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Using a novel method employing a V8 protease digestion coupled with ethyl acetate extraction, we have purified a peptide with C-terminal amide structure from porcine cardiac atrium. The peptide was determined to be Ala-Val-Leu-Gly-Leu-CONH2. According to the sequence, we have raised an antibody and established the radioimmunoassay. Using this radioimmunoassay, we have isolated a novel 14 amino acid peptide where C-terminus was amidated. This peptide was termed amidicin. Amidicin is widely distributed in porcine tissue and is especially abundant in pituitary gland, cardiac ventricle, and spleen. © 2002 Elsevier Science (USA). All rights reserved.
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Expression and immunohistochemical localization of adrenomedullin in the mouse cochlea 査読あり
Tono T., Shimozono M., Kawano H., Asada Y., Kitamura K., Komune S.
ORL 64 ( 3 ) 169 - 172 2002年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：ORL
Adrenomedullin (AM) is a novel hypotensive and vasodilator peptide. It has been shown that AM is biosynthesized in various organs and cells and is suggested to play multiple roles including electrolyte homeostasis and body fluid control. The present study describes for the first time the presence of mRNA for AM and AM-like immunoreactivity in the cochlea. A reverse transcription-polymerase chain reaction (RT-PCR) performed with gene-specific AM primer on total RNA extracted from mouse cochlea revealed a PCR product of the expected size. Immunohistochemical examination showed positive immunostaining in vascular smooth muscle cells of the modiolar arterioles and in the stria vascularis of the cochlea. These results suggest that AM may play a role in the regulation not only of cochlear hemodynamics but also of cochlear fluid dynamics. Copyright © 2002 S. Karger AG, Basel.
DOI： 10.1159/000058020
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Uemura T., Kato J., Kuwasako K., Kitamura K., Kangawa K., Eto T.
Journal of Hypertension 20 ( 6 ) 1209 - 1214 2002年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Hypertension
Objective: Both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). Methods: AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Results: Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH2. Conclusions: AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone. © 2002 Lippincott Williams & Wilkins.
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Rat RAMP domains involved in adrenomedullin binding specificity 査読あり
Kuwasako K., Kitamura K., Onitsuka H., Uemura T., Nagoshi Y., Kato J., Eto T.
FEBS Letters 519 ( 1-3 ) 113 - 116 2002年5月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
When coexpressed with receptor activity-modifying protein (RAMP)2 or -3, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Coexpression of rat (r)CRLR with rRAMP deletion mutants in HEK293T cells revealed that deletion of residues 93-99 from rRAMP2 or residues 58-64 from rRAMP3 significantly inhibits high-affinity [125I]AM binding and AM-evoked cAMP production, despite full cell surface expression of the receptor heterodimer. Apparently, these two seven-residue segments are key determinants of high-affinity agonist binding to rAM receptors and of receptor functionality. Consequently, their deletion yields peptides that are able to serve as negative regulators of AM receptor function. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.