New Therapeutic Approach Using Novel Nuclear Translocating Signaling Protein Against Vascular Remodeling and Atherosclerosis

2008 Fiscal Year Final Research Report

• Project/Area Number: 18390235
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Ehime University
• Principal Investigator: HORIUCHI Masatsugu Ehime University, 大学院・医学系研究科, 教授 (40150338)
• Co-Investigator(Kenkyū-buntansha): IWAI Masaru 愛媛大学, 大学院・医学系研究科, 准教授 (00184854) ; MOGI Masaki 愛媛大学, 大学院・医学系研究科, 講師 (20363236)
• Project Period (FY): 2006 – 2008
• Keywords: レニン・アンジオテンシン系 / 受容体 / 血管リモデリング / 動脈硬化

Research Abstract

アンジオテンシンII受容体タイプ1(AT1)、タイプ2(AT2)受容体は、互いに拮抗して、心血管リモデリングを調節していることが明らかとなってきた。我々は、AT2受容体のC-末端に特異的に結合するATIP(AT2 Receptor Interacting Protein)をクローニングし、ATIPの、血管リモデリングにおける作用をATIP過剰発現(ATIP-Tg)マウスを作製し検討した。血管傷害において、野生型マウスに比べ、血管平滑筋増殖、炎症、酸化ストレス、新生内膜の減少等が認められ、ATIPは血管保護的に作用することが明らかとなった。

Research Products

• [Journal Article] Reduced angiotensin II levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (2009)
  • Author(s): Kawajiri M, Mogi M, Higaki N, Tateishi T, Ohyagi Y, Horiuchi M, Miki T, Kira JI.
  • Journal Title: Acta Neurol Scand (in press)
• [Journal Article] Attenuation of Cuff-Induced Neointimal Formation by Overexpression of Angiotensin II Type2 Receptor-Interacting Protein 1 (2009)
  • Author(s): Fujita T, Mogi M, Min LJ, Iwanami J, Tsukuda K, Sakata A, Okayama H, Iwai M, Nahmias C, Higaki J, Horiuchi M
  • Journal Title: Hypertension 53 Pages: 688-693
• [Journal Article] Prevention of vascular injury by combination of an AT1 receptor blocker, olmesartan, with various calcium antagonists (2009)
  • Author(s): Inaba S, Iwai M, Tomono Y, Senba I, Furuno M, Kanno H, Okayama H, Mogi M, Higaki J, Horiuchi M
  • Journal Title: Am J Hypertens 22 Pages: 145-150
• [Journal Article] Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice (2009)
  • Author(s): Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M
  • Journal Title: Hypertension 53 Pages: 356-362
• [Journal Article] Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes (2009)
  • Author(s): Inaba S, Iwai M, Tomono Y, Senba I, Furuno M, Kanno H, Okayama H, Mogi M, Higaki J, Horiuchi M
  • Journal Title: Stroke 40 Pages: 594-603
• [Journal Article] Angiotensin-converting enzyme(ACE)and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis (2009)
  • Author(s): Kawajiri M, Mogi M, Higaki N, Matsuoka T, Ohyagi Y, Tsukuda K, Kohara K, Horiuchi M, Miki T, Kira J
  • Journal Title: Mult Scler 15 Pages: 262-265
• [Journal Article] Essential role of angiotensin II type 1a receptors in the host vascular wall, but not the bone marrow, in the pathogenesis of angiotensin II-induced atherosclerosis (2008)
  • Author(s): Koga J, Egashira K, Matoba T, Kubo M, Ihara Y, Iwai M, Horiuchi M, Sunagawa K
  • Journal Title: Hypertens Res 31 Pages: 1791-1800
• [Journal Article] Telmisartan prevented cognitive decline partly due to PPAR-gamma activation (2008)
  • Author(s): Mogi M, Li JM, Tsukuda K, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Biochem Biophys Res Commun 375 Pages: 446-449
• [Journal Article] Effect of olmesartan on tissue expression balance between angiotensin II receptor and its inhibitory binding molecule (2008)
  • Author(s): Shigenaga A, Tamura K, Wakui H, Masuda S, Azuma K, Tsurumi-Ikeya Y, Ozawa M, Mogi M, Matsuda M, Uchino K, Kimura K, Horiuchi M, Umemura S
  • Journal Title: Hypertension 52 Pages: 672-678
• [Journal Article] Reduction of angiotensin II in the cerebrospinal fluid of patients with multiple sclerosis (2008)
  • Author(s): Kawajiri M, Mogi M, Osoegawa M, Matsuoka T, Tsukuda K, Kohara K, Horiuchi M, Miki T, Kira JI
  • Journal Title: Mult Scler 14 Pages: 5575-5560
• [Journal Article] Deletion of angiotensin II type 2 receptor attenuates protective effects of bone marrow stromal cell treatment on ischemia-reperfusion brain injury in mice (2008)
  • Author(s): Iwanami J, Mogi M, Li JM, Tsukuda K, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Stroke 39 Pages: 2554-2559
• [Journal Article] Temporary pretreatment with the angiotensin II type 1 receptor blocker, valsartan, prevents ischemic brain damage through an increase in capillary density (2008)
  • Author(s): Li JM, Mogi M, Iwanami J, Min LJ, Tsukuda K, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Stroke 39 Pages: 2029-2036
• [Journal Article] Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition (2008)
  • Author(s): Min LJ, Mogi M, Iwanami J, Li JM, Sakata A, Fujita T, Tsukuda K, Iwai M, Horiuchi M
  • Journal Title: Hypertension 51 Pages: 1339-1344
• [Journal Article] Diabetes-associated cognitive impairment is improved by a calcium channel blocker, nifedipine (2008)
  • Author(s): Tsukuda K, Mogi M, Li JM, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Hypertension 51 Pages: 528-533
• [Journal Article] Akt-FOXO3a signaling affects human endothelial progenitor cell differentiation (2008)
  • Author(s): Mogi M, Walsh K, Iwai M, Horiuchi M
  • Journal Title: Hypertens Res 31 Pages: 153-159
• [Journal Article] Attenuation of focal brain ischemia by telmisartan, an angiotensin II type 1 receptor blocker, in atherosclerotic apolipoprotein E-deficient mice (2008)
  • Author(s): Iwai M, Inaba S, Tomono Y, Kanno H, Iwanami J, Mogi M, Horiuchi M
  • Journal Title: Hypertens Res 31 Pages: 161-168
• [Journal Article] Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models (2008)
  • Author(s): Tomono Y, Iwai M, Inaba S, Mogi M, Horiuchi M
  • Journal Title: Am J Hypertens 21 Pages: 206-212
• [Journal Article] Angiotensin II and III suppress food intake via angiotensin AT(2)receptor and prostaglandin EP(4)receptor in mice (2008)
  • Author(s): Ohinata K, Fujiwara Y, Fukumoto S, Iwai M, Horiuchi M, Yoshikawa M
  • Journal Title: FEBS Lett 582 Pages: 773-777
• [Journal Article] The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes (2008)
  • Author(s): Sakai N, Wada T, Matsushima K, Bucala R, Iwai M, Horiuchi M, Kaneko S
  • Journal Title: J Hypertens 26 Pages: 780-790
• [Journal Article] Hypotensive activity of novokinin, a potent analogue of ovokinin(2-7), is mediated by angiotensin AT(2)receptor and prostaglandin IP receptor (2008)
  • Author(s): Yamada Y, Yamauchi D, Usui H, Zhao H, Yokoo M, Ohinata K, Iwai M, Horiuchi M, Yoshikawa M
  • Journal Title: Peptides 29 Pages: 412-418
• [Journal Article] Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan (2007)
  • Author(s): Mogi M, Tsukuda K, Li JM, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Neuropharmacology 53 Pages: 899-905
• [Journal Article] Amelioration of cognitive impairment in the type-2 diabetic mouse by the angiotensin II type-1 receptor blocker candesartan (2007)
  • Author(s): Tsukuda K, Mogi M, Li JM, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M
  • Journal Title: Hypertension 50(6) Pages: 1099-1105
• [Journal Article] Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis (2007)
  • Author(s): Ihara Y, Egashira K, Nakano K, Ohtani K, Kubo M, Koga J, Iwai M, Horiuchi M, Gang Z, Yamagishi S, Sunagawa K
  • Journal Title: J Mol Cell Cardiol 43 Pages: 455-464
• [Journal Article] Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury (2007)
  • Author(s): Gao X, Iwai M, Inaba S, Tomono Y, Kanno H, Mogi M, Horiuchi M
  • Journal Title: Am J Hypertens 20 Pages: 1170-1175
• [Journal Article] Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence (2007)
  • Author(s): Min LJ, Mogi M, Iwanami J, Li JM, Sakata A, Fujita T, Tsukuda K, Iwai M, Horiuchi M
  • Journal Title: Cardiovasc Res 76 Pages: 506-516
• [Journal Article] Pretreatment with eplerenone reduces stroke volume in mouse middle cerebral artery occlusion model (2007)
  • Author(s): Iwanami J, Mogi M, Okamoto S, Gao XY, Li JM, Min LJ, Ide A, Tsukuda K, Iwai M, Horiuchi M
  • Journal Title: Eur J Pharmacol 566 Pages: 153-159
• [Journal Article] TAK-536, a new AT1 receptor blocker, improves glucose intolerance and adipocyte differentiation (2007)
  • Author(s): Iwai M, Chen R, Imura Y, Horiuchi M
  • Journal Title: Am J Hypertens 20 Pages: 579-586
• [Journal Article] Angiotensin II-induced neural differentiation via angiotensin II type 2(AT2)receptor-MMS2 cascade involving interaction between AT2 receptor-interacting protein and Src homology 2 domain-containing protein-tyrosine phosphatase 1 (2007)
  • Author(s): Li JM, Mogi M, Tsukuda K, Tomochika H, Iwanami J, Min LJ, Nahmias C, Iwai M, Horiuchi M
  • Journal Title: Mol Endocrinol 21 Pages: 499-511
• [Journal Article] Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes : lack of effects in cells from spontaneously hypertensive rats (2006)
  • Author(s): Sonoyama K, Ninomiya H, Igawa O, Kaetsu Y, Furuse Y, Hamada T, Miake J, Li P, Yamamoto Y, Ogino K, Yoshida A, Taniguchi S, Kurata Y, Matsuoka S, Narahashi T, Shiota G, Nozawa Y, Matsubara H, Horiuchi M, Shirayoshi Y, Hisatome I
  • Journal Title: Hypertens Res 29 Pages: 923-993
• [Journal Article] Amlodipine treatment reduces stroke size in apolipoprotein E-deficient mice (2006)
  • Author(s): Mogi M, Iwai M, Chen R, Iwanami J, Ide A, Tsukuda K, Yoshii T, Horiuchi M
  • Journal Title: Am J Hypertens 19 Pages: 1144-1149
• [Journal Article] Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan (2006)
  • Author(s): Iwai M, Li HS, Chen R, Shiuchi T, Wu L, Min LJ, Li JM, Tsuda M, Suzuki J, Tomono Y, Tomochika H, Mogi M, Horiuchi M
  • Journal Title: J Pharmacol Exp Ther 319 Pages: 1081-1087
• [Journal Article] A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade (2006)
  • Author(s): Okada H, Inoue T, Kikuta T, Watanabe Y, Kanno Y, Ban S, Sugaya T, Horiuchi M, Suzuki H
  • Journal Title: Am J Pathol 169 Pages: 1577-1589
• [Journal Article] Attenuation of inflammatory vascular remodeling by angiotensin II type 1 receptor-associated protein (2006)
  • Author(s): Oshita A, Iwai M, Chen R, Ide A, Okumura M, Fukunaga S, Yoshii T, Mogi M, Higaki J, Horiuchi M
  • Journal Title: Hypertension 48 Pages: 671-676
• [Journal Article] Angiotensin II type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2 (2006)
  • Author(s): Mogi M, Li JM, Iwanami J, Min LJ, Tsukuda K, Iwai M, Horiuchi M
  • Journal Title: Hypertension 48 Pages: 141-148
• [Journal Article] Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis (2006)
  • Author(s): Nabeshima Y, Tazuma S, Kanno K, Hyogo H, Iwai M, Horiuchi M, Chayama K
  • Journal Title: Biochem Biophys Res Commun 346 Pages: 658-664
• [Journal Article] Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress (2006)
  • Author(s): Hamai M, Iwai M, Ide A, Tomochika H, Tomono Y, Mogi M, Horiuchi M
  • Journal Title: Neuropharmacology 51 Pages: 822-828
• [Journal Article] The calcium-channel blocker, azelnidipine, enhances the inhibitory action of AT1 receptor blockade on ischemic brain damage (2006)
  • Author(s): Iwai M, Chen R, Ide A, Iwanami J, Tomochika H, Tomono Y, Mogi M, Horiuchi M
  • Journal Title: J Hypertens 24 Pages: 2023-2031
• [Journal Article] A novel function of angiotensin II in skin wound healing. Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor(EGF)-like growth factor-mediated EGF receptor transactivation (2006)
  • Author(s): Yahata Y, Shirakata Y, Tokumaru S, Yang L, Dai X, Tohyama M, Tsuda T, Sayama K, Iwai M, Horiuchi M, Hashimoto K
  • Journal Title: J Biol Chem 69 Pages: 488-494
• [Journal Article] Interacting molecule of AT1 receptor, ATRAP, is colocalized with AT1 receptor in the mouse renal tubules (2006)
  • Author(s): Tsurumi Y, Tamura K, Tanaka Y, Koide Y, Sakai M, Yabana M, Noda Y, Hashimoto T, Kihara M, Hirawa N, Toya Y, Kiuchi Y, Iwai M, Horiuchi M, Umemura S
  • Journal Title: Kidney Int 69 Pages: 488-494
• [Journal Article] Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation (2006)
  • Author(s): Suzuki J, Iwai M, Mogi M, Oshita A, Yoshii T, Higaki J, Horiuchi M
  • Journal Title: Arterioscler Thromb Vasc Biol 26 Pages: 917-921
• [Journal Article] Regression of atherosclerosis by amlodipine via anti-inflammatory and anti-oxidative stress actions (2006)
  • Author(s): Yoshii T, Iwai M, Li Z, Chen R, Ide A, Fukunaga S, Oshita A, Mogi M, Higaki J, Horiuchi M
  • Journal Title: Hypertens Res 29 Pages: 457-466
• [Journal Article] Role of angiotensin II receptor subtypes in conjunctival wound healing (2006)
  • Author(s): Mizoue S, Iwai M, Ide A, Suzuki J, Horiuchi M, Shiraishi A, Ohashi Y
  • Journal Title: Curr Eye Res 31 Pages: 129-136
• [Journal Article] Nifedipine inhibited angiotensin II-induced monocyte chemoattractant protein 1 expression : involvement of inhibitor of nuclear factor kappa B kinase and nuclear factor kappa B-inducing kinase (2006)
  • Author(s): Wu L, Iwai M, Li Z, Li JM, Mogi M, Horiuchi M
  • Journal Title: J Hypertens 24 Pages: 123-130
• [Journal Article] Role of the angiotensin II type2 receptor in arterial remodeling after wire injury in mice
  • Author(s): Yamamoto Y, Watari Y, Brydun A, Yoshizumi M, Akishita M, Horiuchi M, Chayama K, Oshima T, Ozono R
  • Journal Title: Hypertens Res
• [Presentation] Roles of Angiotensin II Receptor Type 2 Receptor Stimulation in Ischemic Brain Damage and Cognition (2009)
  • Author(s): 堀内正嗣
  • Organizer: 第73回日本循環器学会総会・学術集会『トピック』
  • Place of Presentation: 大阪、日本
  • Year and Date: 2009-03-22
• [Presentation] Angiotensin II Type 2 receptor signaling in the brain (2008)
  • Author(s): Horiuchi, M
  • Organizer: ANGIOTENSIN GODON RESEARCH CONFERENCE
  • Place of Presentation: Ventura CA, USA
  • Year and Date: 20080224-29
• [Presentation] 血管老化、虚血性脳障害、アンチエイジングとアンジオテンシンII受容体サブタイプ (2008)
  • Author(s): 堀内正嗣
  • Organizer: 第13回静岡健康・長寿学術フォーラム
  • Place of Presentation: 静岡、日本
  • Year and Date: 2008-11-08
• [Presentation] 組織RAS系、アンジオテンシンII受容体研究の新展開 (2008)
  • Author(s): 堀内正嗣
  • Organizer: 第31回日本高血圧学会総会
  • Place of Presentation: 札幌、日本
  • Year and Date: 2008-10-09
• [Presentation] Roles of angiotensin II type1 and type2 receptors in vascular remodeling and aging, and arteriosclerosis (2008)
  • Author(s): Horiuchi ,M
  • Organizer: 18th Scientific meeting International Society of Hypertension
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2008-06-15
• [Presentation] Renin angiotensin system and aging (2007)
  • Author(s): Horiuchi, M
  • Organizer: 8th CHINA-JAPAN JPINT HYPERTENSION SYMPOSIUM、6TH ASIAN-PACIFIC CONGRESS OF HYPERTENSION
  • Place of Presentation: BEIJING, CHINA
  • Year and Date: 2007-11-18
• [Presentation] 高血圧を知る-そのメカニズムと関連因子-高血圧におけるレニン・アンジオテンシン・アルドステロン系研究の新展開 (2007)
  • Author(s): 堀内正嗣
  • Organizer: 第27回日本医学会総会シンポジウム
  • Place of Presentation: 大阪、日本
  • Year and Date: 2007-04-06
• [Presentation] 血管炎症とレニンーアンジオテンシン系 (2006)
  • Author(s): 堀内正嗣
  • Organizer: 第10回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 福井、日本
  • Year and Date: 2006-11-17
• [Presentation] Amelioration of metabolic syndrome by ARB (2006)
  • Author(s): Horiuchi, M
  • Organizer: ISH 2006 Sapporo Satellite Symposium Metabolic Syndrome, Adipocytokines and Hypertension
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2006-10-23
• [Presentation] Advancing the science of CV protection : Evidence for angiotensin receptor blockade (2006)
  • Author(s): Horiuchi, M
  • Organizer: International Society of Hypertension Novartis Pharma AG Satellite Symposium
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2006-10-17
• [Presentation] Amelioration of metabolic syndrome by valsartan (2006)
  • Author(s): Horiuchi, M
  • Organizer: New Paradigm Shift of CV Continuum-The Roles of RAS-International Society of Hypertension ; Investigator-Initiated Symposium
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2006-10-15
• [Presentation] アンジオテンシン受容体に関する新しい話題AT1 Receptor Associated Protein (2006)
  • Author(s): 堀内正嗣
  • Organizer: 第10回日本心不全学会学術集会JHFS06シンポジウム・パネルディスカッション
  • Place of Presentation: 東京、日本
  • Year and Date: 2006-10-13
• [Book] Current Opinion in Nephrology and Hypertension (2009)
  • Author(s): Mogi M, Iwai M, Horiuchi M
  • Publisher: New insights into the regulation of angiotensin receptors(in press)
• [Book] Hypertension Res (2009)
  • Author(s): Iwanami J, Mogi M, Iwai M, Horiuchi M
  • Total Pages: 1-9
  • Publisher: Inhibition of the renin-angiotensin system and target organ protection
• [Book] Ageing Res Rev (2008)
  • Author(s): Min LJ, Mogi M, Iwai M, Horiuchi M
  • Total Pages: 113-121
  • Publisher: Signaling mechanisms of angiotensin II in regulating vascular senescence
• [Book] Hypertens Res (2008)
  • Author(s): Mogi M, Horiuchi M
  • Total Pages: 1833-1834
  • Publisher: New insight of angiotensin II receptor blocker treatment in cardiac dysfunction using angiotensin-converting enzyme 2-deficient mice
• [Book] Arterioscler Thromb Vasc Biol (2007)
  • Author(s): Mogi M, Iwai M, Horiuchi M
  • Total Pages: 2532-2539
  • Publisher: Emerging concepts of regulation of angiotensin II receptors : new players and targets for traditional receptors
• [Book] Role of NAD(P)H oxidase and its regulation in chronic hypertension (2006)
  • Author(s): Iwai M, Mogi M, Horiuchi M
  • Total Pages: 743-744
  • Publisher: Hypertens Res
• [Book] Hypertension (2006)
  • Author(s): Mogi M, Iwai M, Horiuchi M
  • Total Pages: 1020-1022
  • Publisher: Emerging concept of adipogenesis regulation by the renin-angiotensin system
• [Book] Endocr J (2006)
  • Author(s): Horiuchi M, Mogi M, Iwai M
  • Total Pages: 1-5
  • Publisher: Signaling crosstalk angiotensin II receptor subtypes and insulin
• [Book] Hypertension (2006)
  • Author(s): Mogi M, Iwai M, Horiuchi M
  • Total Pages: 642-643
  • Publisher: New paradigm for brain protection after stroke
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/biochem1/link.html