2002 Fiscal Year Annual Research Report

心筋の機能発現におけるCD38/サイクリックADPリボース情報伝達系の役割

Research Project

Project/Area Number	12470032
Research Institution	Tohoku University
Principal Investigator	高沢伸東北大学, 大学院・医学系研究科, 助教授 (50187944)
Co-Investigator(Kenkyū-buntansha)	加賀谷豊東北大学, 医学部附属病院, 講師 (90250779) 那谷耕司東北大学, 大学院・医学系研究科, 助手 (90202233)
Keywords	CD38 / サイクリックADPリボース / ノックアウトマウス / 筋張力 / 細胞内Ca^<2+> / 心筋 / 心肥大
Research Abstract	病的な心肥大・心不全などの心臓疾患は欧米のみならず、日本における患者数も増加傾向にある。これら本態性心臓疾患の原因は、一部の遺伝子異常によるものを除いて不明な点が多く、その基礎的メカニズムの解明と新しい治療法の開発は、現代医学における最重要課題となっている。本研究では、我々が開発した全身でCD38/サイクリツクADPリボース情報伝達系を欠損する「CD38ノックアウトマウス」を用いて、この情報伝達系が心機能・心筋収縮に果たす役割を解明する。平成14年度の研究では以下の成績を得た。 1.心刺激時・非刺激時の各種ヘモダイナミックパラメーターには正常マウスとCD38ノックアウトマウスで有意な差を認めなかった。 2.正常マウスとCD38ノックアウトマウス心筋の細胞内Ca^<2+>動態に関与する蛋白質の遺伝子発現と蛋白レベルを検討すると、筋小胞体へのCa^<2+>の取り込みを担うSERCA2遺伝子とその蛋白レベルの上昇が認められた。 3.雌マウスの心筋では(2)の変化に加えて、筋小胞体からのCa^<2+>放出チャンネルである2型リアノジン受容体(RyR2)の発現の増大が認められた。一方、雄マウス心筋ではRyR2の発現には変化が認められなかった。以上の結果は前年度までに見出した雄のCD38ノックアウトマウスにおける心肥大はCD38/サイクリックADPリボース系の欠損による心筋機能異常を代償するために細胞内Ca^<2+>のリサイクリングをより有効にするため、SERCA2が代償的に発現増大し、更に雌ではCa^<2+>放出そのものを増大させるためRyR2も発現が増大していると考えられた。雄ではRyR2の代償的発現増大が起こらないので、心筋繊維の肥大によってこれを代償していると考えられた。従って、CD38/サイクリックADPリボース系は心筋機能発現に重要な役割を果たしていることが明らかになった。

Research Products

(28 results)

All Other

All Publications (28 results)

[Publications] Chini EN: "CD38 is the major enzyme responsible for synthesis of nicotinic acid adenine dinucleptide phosphate in mammalian tissues"Biochemical Journal. 362. 125-130 (2002)
[Publications] Takasawa S: "Pancreatic β-cell death, regeneration and insulin secretion : Roles of poly(ADP-ribose) polymerase and cyclic ADP-ribose"International Journal of Experimental Diabetes Research. 3. 79-96 (2002)
[Publications] Okamoto H: "Recent advances in the Oamoto model : The CD38-cyclic ADP-ribose signal system and the Reg-Reg receptor system in β-cells"Diabetes. 51. 462-473 (2002)
[Publications] Unno M: "Production and characterization of Reg knockout mice : Reduced proliferation of pancreatic β-cells in Reg knockout mice"Diabetes. 51. 478-483 (2002)
[Publications] Kadowaki Y: "Reg protein is overexpressed in gastric cancer cells, where it activates a signal transduction pathway that convercges on ERK 1/2 to stimulate growth"FEBS Letters. 530. 59-64 (2002)
[Publications] Petrova RG: "Advanced glycation endoproduct-induced calcium handling impairment in mouse cardiac myocytes"Journal of Molecular and Cellular Cardiology. 34. 1425-1431 (2002)
[Publications] Yonekura H: "Novel splicing variants of receptor for advanced glycation endoproducts (RAGE) expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury"Biochemical Journal. (In press). (2003)
[Publications] Kiji T: "Enhancement of cell viability in cryopreserved rat vascular grafts by administration of regenerating gene (Reg) inducers"Journal of Vascular Research. (In press). (2003)
[Publications] Okamoto H: "Recent advances in physiological and pathological significance of NAD^+ metabolites : Roles of poly(ADP-ribose) and cyclic ADP-ribose in insulin secretion and diabetogenesis"Nutritional Research Review. (In press). (2003)
[Publications] Kaneta T: "Imaging of ischemic viable myocardium using a new [^<18>F]labeled 2-nitroimidazole analog, [^<18>F]FRP17O. Comparison with myocardial perfusion, fatty acid metabolism and glucose metabolism"Journal of Nuclear Medicine. 43. 109-116 (2002)
[Publications] Makabe-Kobayashi Y: "The control effect of histamine on the body temperature and respiratory function in lgE-dependent systemic anaphylaxis"Journal of Allergy and Clinical Immunology. 110. 298-303 (2002)
[Publications] Koyama J: "Evaluation of heart-rate turbulence as a new prognostic marker in patients with chronic heart failure"Circulation Journal. 66. 902-907 (2002)
[Publications] Fukuchi M: "Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary artery"Laboratory Investigation. 82. 1437-1447 (2002)
[Publications] Kagaya Y: "Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualized with 1-[1-^<11>C-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat"Eouropean Journal of Nuclear Medicine. 29. 1516-1522 (2002)
[Publications] Hozawa H: "Post-endsystolic active shortening in the non-ischemic region impairs left ventricular pressure fall in acute ischemic heart"Tohoku Journal of Experimental Medicine. 198. 107-118 (2002)
[Publications] Sakurai K: "Comparison of the efficacy of reperfusion therapies for early mortality from acute myocardial infarction in Japan"Circulation Journal. 67. 209-214 (2003)
[Publications] Koseki Y: "Characteristics and one-year prognosis of medically treated patients with chronic heart failure in Japan. Chronic Heart Failure Analysis Registry in Tohoku District (CHART)"Circulation Journal. (In press). (2003)
[Publications] Sugie T: "Should increasing the dose or adding AT_1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?"Circulation Journal. (In press). (2003)
[Publications] 高沢伸: "Reg-Reg受容体系によるβ細胞のcyclin D1遺伝子の活性化"糖尿病. 45. S169 (2002)
[Publications] 高沢伸: "NAD^+,ポリADPリボース,サイクリックADPリボースによる細胞の死・再生・機能発現"生化学. 74. 620 (2002)
[Publications] Shervani NJ: "Autoantibodies to a pancreatic beta-cell regeneration factor, REG, in diabetes patients"生化学. 74. 819 (2002)
[Publications] 野口直哉: "FK506-Binding Protein 12.6ノックアウトマウスではブドウ糖刺激によるインスリン分泌が低下していた"生化学. 74. 919 (2003)
[Publications] 野口直哉: "遺伝子改変動物を用いたインスリン産生細胞増殖因子Regの機能解析"生化学. 74. 1492 (2003)
[Publications] 野口直哉: "K506結合蛋白質欠損マウスのグルコース刺激によるインスリン分泌の低下"糖尿病. 46(In press). (2003)
[Publications] 岡本宏: "膵β細胞の死から再生へ:Reg-Reg受容体情報伝達系による再生医学"糖尿病. 46(In press). (2003)
[Publications] 野口直哉: "Cyclic ADP-riboseによる小胞体からのCa^<2+>放出機構:FK506結合蛋白質の関与"Diabetes Frontier. (In press). (2003)
[Publications] Okamoto H: "The mechanism of β-cell regeneration by Reg protein : Experiments with Reg knockout mouse islets"Diabetes. 52(In press). (2003)
[Publications] Takasawa S: "Cyclic ADP-ribose and NAADP : Structure, Metabolism and Physiological Functions"Kluwer. 31 (2002)

2002 Fiscal Year Annual Research Report

心筋の機能発現におけるCD38/サイクリックADPリボース情報伝達系の役割

Principal Investigator

高沢 伸 東北大学, 大学院・医学系研究科, 助教授 (50187944)

Research Products

[Publications] Chini EN: "CD38 is the major enzyme responsible for synthesis of nicotinic acid adenine dinucleptide phosphate in mammalian tissues"Biochemical Journal. 362. 125-130 (2002)

[Publications] Takasawa S: "Pancreatic β-cell death, regeneration and insulin secretion : Roles of poly(ADP-ribose) polymerase and cyclic ADP-ribose"International Journal of Experimental Diabetes Research. 3. 79-96 (2002)

[Publications] Okamoto H: "Recent advances in the Oamoto model : The CD38-cyclic ADP-ribose signal system and the Reg-Reg receptor system in β-cells"Diabetes. 51. 462-473 (2002)

[Publications] Unno M: "Production and characterization of Reg knockout mice : Reduced proliferation of pancreatic β-cells in Reg knockout mice"Diabetes. 51. 478-483 (2002)

[Publications] Kadowaki Y: "Reg protein is overexpressed in gastric cancer cells, where it activates a signal transduction pathway that convercges on ERK 1/2 to stimulate growth"FEBS Letters. 530. 59-64 (2002)

[Publications] Petrova RG: "Advanced glycation endoproduct-induced calcium handling impairment in mouse cardiac myocytes"Journal of Molecular and Cellular Cardiology. 34. 1425-1431 (2002)

[Publications] Yonekura H: "Novel splicing variants of receptor for advanced glycation endoproducts (RAGE) expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury"Biochemical Journal. (In press). (2003)

[Publications] Kiji T: "Enhancement of cell viability in cryopreserved rat vascular grafts by administration of regenerating gene (Reg) inducers"Journal of Vascular Research. (In press). (2003)

[Publications] Okamoto H: "Recent advances in physiological and pathological significance of NAD^+ metabolites : Roles of poly(ADP-ribose) and cyclic ADP-ribose in insulin secretion and diabetogenesis"Nutritional Research Review. (In press). (2003)

[Publications] Kaneta T: "Imaging of ischemic viable myocardium using a new [^<18>F]labeled 2-nitroimidazole analog, [^<18>F]FRP17O. Comparison with myocardial perfusion, fatty acid metabolism and glucose metabolism"Journal of Nuclear Medicine. 43. 109-116 (2002)

[Publications] Makabe-Kobayashi Y: "The control effect of histamine on the body temperature and respiratory function in lgE-dependent systemic anaphylaxis"Journal of Allergy and Clinical Immunology. 110. 298-303 (2002)

[Publications] Koyama J: "Evaluation of heart-rate turbulence as a new prognostic marker in patients with chronic heart failure"Circulation Journal. 66. 902-907 (2002)

[Publications] Fukuchi M: "Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary artery"Laboratory Investigation. 82. 1437-1447 (2002)

[Publications] Kagaya Y: "Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualized with 1-[1-^<11>C-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat"Eouropean Journal of Nuclear Medicine. 29. 1516-1522 (2002)

[Publications] Hozawa H: "Post-endsystolic active shortening in the non-ischemic region impairs left ventricular pressure fall in acute ischemic heart"Tohoku Journal of Experimental Medicine. 198. 107-118 (2002)

[Publications] Sakurai K: "Comparison of the efficacy of reperfusion therapies for early mortality from acute myocardial infarction in Japan"Circulation Journal. 67. 209-214 (2003)

[Publications] Koseki Y: "Characteristics and one-year prognosis of medically treated patients with chronic heart failure in Japan. Chronic Heart Failure Analysis Registry in Tohoku District (CHART)"Circulation Journal. (In press). (2003)

[Publications] Sugie T: "Should increasing the dose or adding AT_1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?"Circulation Journal. (In press). (2003)

[Publications] 高沢 伸: "Reg-Reg受容体系によるβ細胞のcyclin D1遺伝子の活性化"糖尿病. 45. S169 (2002)

[Publications] 高沢 伸: "NAD^+,ポリADPリボース,サイクリックADPリボースによる細胞の死・再生・機能発現"生化学. 74. 620 (2002)

[Publications] Shervani NJ: "Autoantibodies to a pancreatic beta-cell regeneration factor, REG, in diabetes patients"生化学. 74. 819 (2002)

[Publications] 野口直哉: "FK506-Binding Protein 12.6ノックアウトマウスではブドウ糖刺激によるインスリン分泌が低下していた"生化学. 74. 919 (2003)

[Publications] 野口直哉: "遺伝子改変動物を用いたインスリン産生細胞増殖因子Regの機能解析"生化学. 74. 1492 (2003)

[Publications] 野口直哉: "K506結合蛋白質欠損マウスのグルコース刺激によるインスリン分泌の低下"糖尿病. 46(In press). (2003)

[Publications] 岡本 宏: "膵β細胞の死から再生へ:Reg-Reg受容体情報伝達系による再生医学"糖尿病. 46(In press). (2003)

[Publications] 野口直哉: "Cyclic ADP-riboseによる小胞体からのCa^<2+>放出機構:FK506結合蛋白質の関与"Diabetes Frontier. (In press). (2003)

[Publications] Okamoto H: "The mechanism of β-cell regeneration by Reg protein : Experiments with Reg knockout mouse islets"Diabetes. 52(In press). (2003)

[Publications] Takasawa S: "Cyclic ADP-ribose and NAADP : Structure, Metabolism and Physiological Functions"Kluwer. 31 (2002)

高沢伸東北大学, 大学院・医学系研究科, 助教授 (50187944)

[Publications] 高沢伸: "Reg-Reg受容体系によるβ細胞のcyclin D1遺伝子の活性化"糖尿病. 45. S169 (2002)

[Publications] 高沢伸: "NAD^+,ポリADPリボース,サイクリックADPリボースによる細胞の死・再生・機能発現"生化学. 74. 620 (2002)

[Publications] 岡本宏: "膵β細胞の死から再生へ:Reg-Reg受容体情報伝達系による再生医学"糖尿病. 46(In press). (2003)