1999 Fiscal Year Annual Research Report

遺伝子変異動物を用いた心血管リモデリングの分子機構に関する多施設共同研究

Research Project

Project/Area Number	11694265
Research Category	Grant-in-Aid for Scientific Research (A)
Research Institution	Kyoto University
Principal Investigator	中尾一和京都大学, 大学院・医学研究科, 教授 (00172263)
Co-Investigator(Kenkyū-buntansha)	伊藤裕京都大学, 大学院・医学研究科, 助手 (40252457) 菅原照京都大学, 大学院・医学研究科, 助手 (00312223) 斎藤能彦京都大学, 大学院・医学研究科, 助教授 (30250260) 小川佳宏京都大学, 大学院・医学研究科, 助手 (70291424) 向山政志京都大学, 生産開発科学研究所, 主任研究員 (40270558)
Keywords	ナトリウム利尿ペプチド / アンジオテンシンII / エンドセリン / トランスジェニックマウス / ノックアウトマウス / 心臓 / 血管 / 腎臓
Research Abstract	我々は、血液を送り出すポンプであり管と考えられていた心臓や血管が、種々の生理活性物質を生合成、分泌していることを明らかにし、心臓血管内分泌学という概念を打ち出した。すなわち、強力な血管平滑筋弛緩作用を有するナトリウム利尿ペプチドファミリーのうちANP、BNPは心臓から分泌され、一方CNPが血管内皮細胞から分泌されることを明らかにした。また、血管内皮から強力な血管平滑筋収縮作用を有するエンドセリンやアンジオテンシンIIが産生、分泌されることも明らかになった。また、我々はエンドセリン受容体に関し、血管平滑筋細胞に発現し、血管収縮に関与するETA受容体及び血管内皮細胞に発現し、血管弛緩に関与するETB受容体の双方の遺伝子構造の決定に成功した。また我々の研究協力者により、2種類存在する膜型グアニル酸シクラーゼそのものであるナトリウム利尿ペプチド受容体(GC-A及びGC-B)の構造決定がなされた。また、アンジオテンシンII受容体(AT1及びAT2)のうち、AT2受容体のクローニングがなされた。本年度は、既に保有しているBNPトランスジェニックマウス(Tg)、GC-Aノックアウトマウス(K/o)、AT1受容体、AT2受容体K/o、AT1受容体Tg、ET-A受容体、ET-B受容体K/oに加えBNP及びCNP K/oを作製した。更に、BNP K/oに対し大動脈結紮圧負荷モデルを作成し、心臓の線維化の促進を確認した。また、CNP K/oにおいて著しい成長遅延と早期の死亡を認めた。更にGC-A K/oにおいて冠動脈結紮心筋梗塞モデルを作成し、心筋病変の増悪を認めた。また、AT1受容体Tgにおいても同様の検討を行った。BNPTgとGC-A K/oとの交配を行った。現在、このBNP Tg/GC-A K/oマウスについて、GC-A K/oに認めた形質に関し解析中である。ET-B受容体ノックアウトマウスを用い、ET-Bを介した血圧電解質調節における意義を明らかにした。

Research Products
(41 results)

All Other

All Publications (41 results)

[Publications] H.Itoh et al.: "Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor γ"Clin. Exp. Pharmacol. Physiol.. 26. 558-560 (1999)
[Publications] K.Moriyama et al.: "A case of Hashimoto's thyroiditis with markedly elevated serum hyroglobulin and evidence of its influence on the measurement of anti thyroglobulin antibody by highly sensitive assays"Endocr. J.. 46. 687-693 (1999)
[Publications] M.Shintani et al.: "Thyrotropin decreases leptin production in rat adipocytes"Metabolism. 48. 1570-1574 (1999)
[Publications] T.Akamizu et al.: "Characterization of recombinant monoclonal antithyrotropin receptor antibodies (TSHRAbs) derived from lymphocytes of patients with Graves' disease: Epitope and binding study of two stimulatory TSHRAbs"Endocrinology. 140. 1594-1601 (1999)
[Publications] Y.Nakamura et al.: "Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans"J. Clin. Endocrinol. Metab.. 84. 1414-1419 (1999)
[Publications] T.Tanaka et al.: "Down-regulation of peroxisome proliferator-activated receptor γ expression by inflammatory cytokines and its reversal by thiazolidinediones"Diabetologia. 42. 702-710 (1999)
[Publications] R.Ishibashi et al.: "Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions"Kidney Int.. 56. 589-600 (1999)
[Publications] K.Mori et al.: "Isolation and characterization of CA XIV, a novel membrane-bound carbonic anhydrase from mouse kidney"J. Biol. Chem.. 274. 15701-15705 (1999)
[Publications] K.Chin et al.: "Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy"Circulation. 100. 706-712 (1999)
[Publications] H.Itoh et al.: "Basic fibroblast growth factor decrease clearance receptor of natriuretic peptide feto-placental artery endothelium"Am. J. Physiol.. 46. R541-R547 (1999)
[Publications] H.Itoh et al.: "Role of the guanylate cyclase system in the regulation of ovine uterine arterial blood flow during pregnancy, a review"Trophoblast research. 13. 301-309 (1999)
[Publications] H.Masuzaki et al.: "Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation"Diabetes. 48. 1615-1622 (1999)
[Publications] Y.Ogawa et al.: "Clinical implication of leptin, the obese gene product"Intern. Med.. 38. 210-212 (1999)
[Publications] M.Nakayama et al.: "T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm"Circulation. 99. 2864-2870 (1999)
[Publications] N.Satoh et al.: "Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion"Diabetes. 48. 1787-1793 (1999)
[Publications] K.Kuwahara et al.: "Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro"Circulation. 100. 1116-1124 (1999)
[Publications] M.Ishikawa et al.: "Heart-specific increase in cardiotrophin-1 gene expression precedes establishment of ventricular hypertrophy in genetically hypertensive rats"J. Hypertens.. 17. 807-816 (1999)
[Publications] K.Kuwahara et al.: "The effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic response in neonatal rat cardiac myocyte-possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophy"FEBS Lett.. 452. 314-318 (1999)
[Publications] J.Ozaki et al.: "Enzmatic inactivation of major circulating forms of atrial and brain natriuretic peptides"Eur. J. Pharmacol.. 370. 307-312 (1999)
[Publications] Y.Sasaki et al.: "Production of thrombopoietin by human carcinomas and its novel isoforms"Blood. 94. 1952-1960 (1999)
[Publications] M.Yamasaki et al.: "FGF-10 is a growth factor for preadipocytes in white adipose tissue"Biochem. Biophys. Res. Commun.. 258. 109-112 (1999)
[Publications] Y.Ogawa et al.: "Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin"Diabetes. 48. 1822-1829 (1999)
[Publications] K.Ebihara et al.: "Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action"Diabetes. 48. 2028-2033 (1999)
[Publications] M.Suda et al.: "C-type natriuretic peptide/guanylate cyclase B system in rat osteogenic ROB-C26 cells and its down-regulation by dexamethazone"Calcif. Tissue Int.. 65. 472-478 (1999)
[Publications] K.Yahata et al.: "Identification of a novel R642C mutation in Na/CL cotransporter with Gitelman's syndrome"Am. J. Kidney Dis.. 34. 845-853 (1999)
[Publications] E.Harada et al.: "Effect of interleukin-1 β on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture"J. Mol. Cell Cardiol.. 31. 1997-2006 (1999)
[Publications] M.Suda et al.: "Prostaglandin E2 (PGE2) induces the c-fos and c-jun expressions via EPI subtype of PGE receptor in mouse osteoblastic NC3T3-E1 cells"Calcif.Tissue Int.. 66. 217-223 (2000)
[Publications] I.Hamanaka et al.: "Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart"Am. Physiol. Soc.. (in press). (2000)
[Publications] S.Yura et al.: "Accelerated puberty and late onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin"J. Clin. Invest.. (in press). (2000)
[Publications] T.Nagae et al.: "Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: Cloning and upregulation in obstructive nephropathy"Biochem. Biophys. Res. Commun.. (in press). (2000)
[Publications] N.Tamura et al.: "Cardiac fibrosis in mice lacking brain natriuretic peptide"Proc. Natl. Acad. Sci. USA. (in press). (2000)
[Publications] E.Ogawa et al.: "Outside-in signaling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes"J. Mol. Cell. Cardiol.. (in press). (2000)
[Publications] Y.Sakuma et al.: "Crucial involvement of the EP4 subtype of prostaglandin E(PGE) receptor in osteoclast formation by pro-inflammatory cytokines and lipopolysaccharide"J. Bone Miner. Res.. (in press). (2000)
[Publications] Y.Moriyama et al.: "The plasma levels of dehydroepiandrosterone sulfate (DHEAS) are decreased in patients with chronic heart failure in proportion to the severity"J. Clin. Endocrinol. Metab.. (in press). (2000)
[Publications] P-S.Gao et al.: "Variants of NOS1, NOS2 and NOS3 genes in asthmatics"Biochem. Biophys. Res. Commun.. 267. 761-763 (2000)
[Publications] N.Sawada et al.: "Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries"Circulation. (in press). (2000)
[Publications] M.Aizawa-Abe et al.: "Pathophysiologic role of leptin in obesity-related hypertension"J. Clin. Invest.. (in press). (2000)
[Publications] M.Kasahara et al.: "Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation"J. Am. Soc. Nephrol.. (in press). (2000)
[Publications] T-H.Chun et al.: "Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin"J. Hypertens.. (in press). (2000)
[Publications] M.Shintani et al.: "Down-regulation of leptin by free fatty acids in rat adipocytes: Effects of triacsin C, palmitate and 2-bromopalmitate"Metabolism. (in press). (2000)
[Publications] K.Ohmura et al.: "Emergence of T,B and myeloid lineage committed as well as multipotent hematopoietic progenitors in the AGM region of day 10 fetuses of the mouse"J. Immunol.. (in press). (2000)

1999 Fiscal Year Annual Research Report

遺伝子変異動物を用いた心血管リモデリングの分子機構に関する多施設共同研究

Principal Investigator

中尾 一和 京都大学, 大学院・医学研究科, 教授 (00172263)

Research Products

[Publications] H.Itoh et al.: "Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor γ"Clin. Exp. Pharmacol. Physiol.. 26. 558-560 (1999)

[Publications] K.Moriyama et al.: "A case of Hashimoto's thyroiditis with markedly elevated serum hyroglobulin and evidence of its influence on the measurement of anti thyroglobulin antibody by highly sensitive assays"Endocr. J.. 46. 687-693 (1999)

[Publications] M.Shintani et al.: "Thyrotropin decreases leptin production in rat adipocytes"Metabolism. 48. 1570-1574 (1999)

[Publications] T.Akamizu et al.: "Characterization of recombinant monoclonal antithyrotropin receptor antibodies (TSHRAbs) derived from lymphocytes of patients with Graves' disease: Epitope and binding study of two stimulatory TSHRAbs"Endocrinology. 140. 1594-1601 (1999)

[Publications] Y.Nakamura et al.: "Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans"J. Clin. Endocrinol. Metab.. 84. 1414-1419 (1999)

[Publications] T.Tanaka et al.: "Down-regulation of peroxisome proliferator-activated receptor γ expression by inflammatory cytokines and its reversal by thiazolidinediones"Diabetologia. 42. 702-710 (1999)

[Publications] R.Ishibashi et al.: "Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions"Kidney Int.. 56. 589-600 (1999)

[Publications] K.Mori et al.: "Isolation and characterization of CA XIV, a novel membrane-bound carbonic anhydrase from mouse kidney"J. Biol. Chem.. 274. 15701-15705 (1999)

[Publications] K.Chin et al.: "Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy"Circulation. 100. 706-712 (1999)

[Publications] H.Itoh et al.: "Basic fibroblast growth factor decrease clearance receptor of natriuretic peptide feto-placental artery endothelium"Am. J. Physiol.. 46. R541-R547 (1999)

[Publications] H.Itoh et al.: "Role of the guanylate cyclase system in the regulation of ovine uterine arterial blood flow during pregnancy, a review"Trophoblast research. 13. 301-309 (1999)

[Publications] H.Masuzaki et al.: "Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation"Diabetes. 48. 1615-1622 (1999)

[Publications] Y.Ogawa et al.: "Clinical implication of leptin, the obese gene product"Intern. Med.. 38. 210-212 (1999)

[Publications] M.Nakayama et al.: "T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm"Circulation. 99. 2864-2870 (1999)

[Publications] N.Satoh et al.: "Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion"Diabetes. 48. 1787-1793 (1999)

[Publications] K.Kuwahara et al.: "Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro"Circulation. 100. 1116-1124 (1999)

[Publications] M.Ishikawa et al.: "Heart-specific increase in cardiotrophin-1 gene expression precedes establishment of ventricular hypertrophy in genetically hypertensive rats"J. Hypertens.. 17. 807-816 (1999)

[Publications] K.Kuwahara et al.: "The effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic response in neonatal rat cardiac myocyte-possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophy"FEBS Lett.. 452. 314-318 (1999)

[Publications] J.Ozaki et al.: "Enzmatic inactivation of major circulating forms of atrial and brain natriuretic peptides"Eur. J. Pharmacol.. 370. 307-312 (1999)

[Publications] Y.Sasaki et al.: "Production of thrombopoietin by human carcinomas and its novel isoforms"Blood. 94. 1952-1960 (1999)

[Publications] M.Yamasaki et al.: "FGF-10 is a growth factor for preadipocytes in white adipose tissue"Biochem. Biophys. Res. Commun.. 258. 109-112 (1999)

[Publications] Y.Ogawa et al.: "Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin"Diabetes. 48. 1822-1829 (1999)

[Publications] K.Ebihara et al.: "Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action"Diabetes. 48. 2028-2033 (1999)

[Publications] M.Suda et al.: "C-type natriuretic peptide/guanylate cyclase B system in rat osteogenic ROB-C26 cells and its down-regulation by dexamethazone"Calcif. Tissue Int.. 65. 472-478 (1999)

[Publications] K.Yahata et al.: "Identification of a novel R642C mutation in Na/CL cotransporter with Gitelman's syndrome"Am. J. Kidney Dis.. 34. 845-853 (1999)

[Publications] E.Harada et al.: "Effect of interleukin-1 β on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture"J. Mol. Cell Cardiol.. 31. 1997-2006 (1999)

[Publications] M.Suda et al.: "Prostaglandin E2 (PGE2) induces the c-fos and c-jun expressions via EPI subtype of PGE receptor in mouse osteoblastic NC3T3-E1 cells"Calcif.Tissue Int.. 66. 217-223 (2000)

[Publications] I.Hamanaka et al.: "Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart"Am. Physiol. Soc.. (in press). (2000)

[Publications] S.Yura et al.: "Accelerated puberty and late onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin"J. Clin. Invest.. (in press). (2000)

[Publications] T.Nagae et al.: "Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: Cloning and upregulation in obstructive nephropathy"Biochem. Biophys. Res. Commun.. (in press). (2000)

[Publications] N.Tamura et al.: "Cardiac fibrosis in mice lacking brain natriuretic peptide"Proc. Natl. Acad. Sci. USA. (in press). (2000)

[Publications] E.Ogawa et al.: "Outside-in signaling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes"J. Mol. Cell. Cardiol.. (in press). (2000)

[Publications] Y.Sakuma et al.: "Crucial involvement of the EP4 subtype of prostaglandin E(PGE) receptor in osteoclast formation by pro-inflammatory cytokines and lipopolysaccharide"J. Bone Miner. Res.. (in press). (2000)

[Publications] Y.Moriyama et al.: "The plasma levels of dehydroepiandrosterone sulfate (DHEAS) are decreased in patients with chronic heart failure in proportion to the severity"J. Clin. Endocrinol. Metab.. (in press). (2000)

[Publications] P-S.Gao et al.: "Variants of NOS1, NOS2 and NOS3 genes in asthmatics"Biochem. Biophys. Res. Commun.. 267. 761-763 (2000)

[Publications] N.Sawada et al.: "Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries"Circulation. (in press). (2000)

[Publications] M.Aizawa-Abe et al.: "Pathophysiologic role of leptin in obesity-related hypertension"J. Clin. Invest.. (in press). (2000)

[Publications] M.Kasahara et al.: "Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation"J. Am. Soc. Nephrol.. (in press). (2000)

[Publications] T-H.Chun et al.: "Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin"J. Hypertens.. (in press). (2000)

[Publications] M.Shintani et al.: "Down-regulation of leptin by free fatty acids in rat adipocytes: Effects of triacsin C, palmitate and 2-bromopalmitate"Metabolism. (in press). (2000)

[Publications] K.Ohmura et al.: "Emergence of T,B and myeloid lineage committed as well as multipotent hematopoietic progenitors in the AGM region of day 10 fetuses of the mouse"J. Immunol.. (in press). (2000)

中尾一和京都大学, 大学院・医学研究科, 教授 (00172263)