The influence and the mechanism of hypercholesterolemia to cerebral homeostasis

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590057
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Chiba University
• Principal Investigator: ISHII Itsuko 千葉大学, 医学部附属病院, 教授 (00202929)
• Project Period (FY): 2010 – 2012
• Keywords: 脳 / コレステロール / 血液脳関門 / 血管透過性

Research Abstract

We have found that cholesterol is accumulated in a brain and renal functions reduce in mice fed a high cholesterol diet. In this research, it was aimed to clarify the mechanism of increase of the vascular permeability by hypercholesterolemia of mice fed a high cholesterol diet. In the high cholesterol fed-mice, the activity of MMP9 in blood increased intentionally. The ratio of the lymphocyte in blood decreased, and that of neutrophils statistically increased. These data suggested that the permeability of BBB might be increased by MMP9 derived from neutrophils which degrades ZO-1.When mice fed a high cholesterol diet were treated ezetimibe or cholestyramine, the blood cholesterol level, MMP9 level and the ratio of the neutrophil in blood decreased. Especially, the cholestyramine which induces bile acid excretion also recovered HDL level, inhibition of induction of BBB permeability was high, and a part of renal function was also recovered. Since we found that acrolein increased in blood of hypercholesterolemia of mice fed a high cholesterol diet, we clarify whether lipoproteins modified with acrolien induces to form foam cells from macrophages.

Research Products

• [Journal Article] Acrolein-conjugated low-density lipoprotein induces macrophage foam cell formation (2013)
  • Author(s): Watanabe K, Nakazato Y, Saiki R, Igarashi K, Kitada M, Ishii I
  • Journal Title: Atherosclerosis Volume: 227(1) Pages: 51-7
  • Peer Reviewed
• [Journal Article] Inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid, an acrolein- glutathione metabolite (2012)
  • Author(s): Yoshida, M., Mikami, T., Higashi, K., Saiki, R., Mizoi, M., Fukuda, K., Nakamura, T., Ishii, I., Nishimura, K., Toida, T., Tomitori, H., Kashiwagi, K., and Igarashi, K.
  • Journal Title: Clin. Chim.Acta Volume: 413(7-8) Pages: 753-9
  • Peer Reviewed
• [Journal Article] Nitroxide derivatives for imaging of hypercholesterolemia-induced kidney dysfunction and assessing the effectiveness of anti-lipidemicdrugs (2011)
  • Author(s): Tomizawa, A., Hadjidekov, G., Ishii, I., Bakalova, R., Zhelev, Z., Aoki, I., Saga, T., and Kitada, M.
  • Journal Title: Mol. Pharm Volume: 8 Pages: 1962-9
  • Peer Reviewed
• [Journal Article] Carbamoyl- PROXYL-enhanced MRI detects very small disruptions in brain vascular permeability induced by dietary cholesterol (2011)
  • Author(s): Tomizawa, A., Ishii, I., Zhelev, Z., Aoki, I., Shibata, S., Kitada, M., and Bakalova, R.
  • Journal Title: Biochim. Biophys. Acta -Gen. Subjects Volume: 1810 Pages: 1309-16
  • Peer Reviewed
• [Presentation] アクロレイン化LDLによるマクロファージの泡沫化経路の検討 (2013)
  • Author(s): 渡辺健太,五十嵐一衛,石井伊都子
  • Organizer: 日本薬学会第133年会.(要旨集CD-ROM29pmC-232S,2013)
  • Year and Date: 20130000
• [Presentation] Kefiran Reduces Atherosclerosis in Rabbits Fed a High Cholesterol Diet (Symposium). The 8th Congress of Toxicology in Developing Countries (8CTDC) (2012)
  • Author(s): Ishii, I.
  • Organizer: Symposium). The 8^<th> Congress of Toxicology in Developing Countries (8CTDC) September 10-13, 2012 - Bangkok, Thailand (Abstract p19, 2012)
  • Place of Presentation: Bangkok, Thailand (Abstractp19, 2012)
  • Year and Date: 20120910-13
• [Presentation] 食餌性高コレステロール血症由来腎機能障害に対する MR イメージングによる 抗高脂血症薬の効果の評価 (2011)
  • Author(s): 石井伊都子, Rumiana Bakalova, ZhivkoZhelev, 青木伊知男, 北田光一
  • Organizer: Nitroxide derivatives for imaging of hypercholesterolemia- induced kidney dysfunction and assessing the effectiveness of anti-lipidemic drugs. 第84 会日本生化学会大会. [要 旨集 4T8p-2(4P-0049),2011]
  • Year and Date: 20110000
• [Presentation] 食餌性高コレステロール血症がマウス腎臓に及ぼす影響. (2011)
  • Author(s): 野村里香,石井伊都子,富澤宏之,藤内真実,BakalovaRumiana,有吉範高,北田光一
  • Organizer: 日本薬学会第131年会.(要旨集3p84,2011)
  • Year and Date: 20110000