JP5884105B2 - 酸化ldl阻害剤 - Google Patents
酸化ldl阻害剤 Download PDFInfo
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- JP5884105B2 JP5884105B2 JP2013557577A JP2013557577A JP5884105B2 JP 5884105 B2 JP5884105 B2 JP 5884105B2 JP 2013557577 A JP2013557577 A JP 2013557577A JP 2013557577 A JP2013557577 A JP 2013557577A JP 5884105 B2 JP5884105 B2 JP 5884105B2
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- oxidized ldl
- ldl
- cells
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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Description
(1)Del−1は、脳や肺組織において発現が高い(例えば、非特許文献1を参照のこと。)。
(2)Del−1は、Del−1のC末端のC1、C2ドメインでフォスファチジルセリン(PS)に結合し、マクロファージのアポトーシス細胞貪食を促進する(例えば、非特許文献2参照のこと。)。
(3)Del−1は、血管新生を促進する(例えば、非特許文献3参照のこと。)。
(4)Del−1は、白血球と内皮細胞との接着を抑制する(抗炎症作用)(例えば、非特許文献1を参照のこと。)。
(5)損傷血管や低酸素状態でDel−1の発現が誘導される(例えば、非特許文献4および5を参照のこと。)。
(a)配列番号1に示されるアミノ酸配列からなるタンパク質、または、
(b)配列番号1に示されるアミノ酸配列において、1個もしくは数個のアミノ酸が置換、欠失、挿入、もしくは付加されたアミノ酸配列からなり、且つ酸化LDL阻害活性を有するタンパク質であってもよい。
本発明の酸化LDL阻害剤は、Del−1(Developmental endothelial locus-1)タンパク質を有効成分として含有することを特徴としている。
本願発明の薬学的組成物は、上述の本発明の酸化LDL阻害剤を含有することを特徴としている。本発明の薬学的組成物によれば、酸化LDLの細胞内への取り込みを阻害し、かつ酸化LDL依存的な細胞反応をも阻害することができるため、酸化LDLが原因で引き起こされる様々な疾患、とりわけ動脈硬化性疾患の治療または予防に奏効することが期待される。
(方法)
(1)Del−1
実験に使用したヒト由来Del−1は、R&D社より購入した。当該Del−1は、C末端側にHisタグを付加した組換えタンパクで、CHO細胞にて発現させ、精製されたものである。
健常人からACD(acid-citrate-dextrose)含有バッファーが添加されている採血管に採取した血液から血漿を分離回収した。得られた血漿に臭化カリウムを加えて比重を1.019に調整した後、58,000rpmで20時間遠心分離処理を行った。下層を回収し、臭化カリウムにて比重を1.063に調整した後、58,000rpmで20時間遠心分離処理を行った。超遠心機は、Beckman社製のL−80を使用した。
BCA Protein Assay Kit (Pierce社製)を用いて精製ヒトLDLのタンパク質量を測定し、濃度が3mg/mlとなるようにPBS(−)で調整した溶液に、硫酸銅を7.5μMとなるように添加した後、37℃、5%CO2インキュベーター内で16時間インキュベートした。続いて、この溶液を、2mM EDTAを含有する0.15M塩化ナトリウム溶液を外液として透析し(外液4回交換)、ヒト酸化LDLとした。なお、実施例の結果を示す図において、酸化LDLを「oxLDL」と表記する場合がある。
384 well プレート(greiner社製)に、抗ApoB抗体(Bindingsite社製)を固相化し、25%ブロックエース(大日本住友製薬社製)でブロッキングを行った後、酸化LDLまたはLDLを結合させた。PBS(−)でプレートを2回洗浄後、溶液(10mM HEPES,150mM NaCl,pH7.4)で希釈したDel−1を添加し、室温で1時間反応させ、結合したDel−1を抗Hisタグ抗体(Invitrogen社)で検出した。図2(a)に、LDLまたは酸化LDLに結合したDel−1のELISAによる検出原理を説明する概念図を示す。
図2(b)に、LDLまたは酸化LDLに結合したDel−1をELISAによって検出した結果を示す。
(方法)
(1)DiI標識LDLまたはDiI標識酸化LDL(DiI−oxLDL)の作製
ヒトLDLまたはヒト酸化LDLを、2mM EDTAを含有する0.15M塩化ナトリウム溶液を用いて希釈し、1mg/mlとなるように調整した。この溶液に、終濃度が0.3mg/mlとなるようにDiI(D282,Invitrogen社製)を、終濃度が5mg/mlとなるようにLipoprotein deficient serum (Sigma社製)を、それぞれ添加し、37℃で18時間反応させた。DiIは、30μg/mlとなるようにDMSOに懸濁した溶液を用いた。
10%FBSを含むDMEM培地(GIBCO社)を用い、37℃、5%CO2条件下で、48時間培養された各種細胞を本実施例に用いた。各種受容体発現細胞は、以下のようにして作成された。
LONZA社より購入した。培養には、EGM−2培地(LONZA社製)を用い、37℃、5%CO2条件下で培養を行った。実験には、継代回数7回以下の細胞を使用した。
10%FBSを含む20μMの2-Mercaptoethanolを含むRPMI1940培地(GIBCO社製)を用い、37℃、5%CO2条件下で培養を行った。実験には、100nM PMA(Phorbol 12Myristate 13Acetate)存在下で72時間培養し、マクロファージ様に分化誘導させた細胞を使用した。
384 well プレート(greiner社製)に撒いた各種細胞を、無血清DMEM培地で洗浄後、Del−1と、DiI標識LDLまたはDiI標識酸化LDLとの混合液を加え、37℃、5%CO2条件下で反応させた。細胞に取り込まれたDiI標識LDLまたはDiI標識酸化LDLの蛍光シグナルを、INCell Analyzer 1000 (GE healthcare社製)で検出し、定量評価した。
酸化LDLまたはLDLの、LDL受容体発現細胞またはLOX−1発現細胞への取り込みに対するDel−1の影響を評価した結果を図3に示した。図3(a)はLDL受容体発現細胞に対して、Del−1の非存在下でDiI標識LDLを取り込ませた細胞の蛍光顕微鏡像であり、図3(b)はDel−1の存在下(30μg/ml)でDiI標識LDLを取り込ませた細胞の蛍光顕微鏡像である。また図3(c)はLOX−1発現細胞に対して、Del−1の非存在下でDiI標識酸化LDLを取り込ませた細胞の蛍光顕微鏡像であり、図3(d)はDel−1の存在下(30μg/ml)でDiI標識酸化LDLを取り込ませた細胞の蛍光顕微鏡像である。
(方法)
(1)酸化LDLによる細胞反応を調べるために、TetOn hLOX-1-V5-His / HA-Flag hAT1 / CHO 細胞(「LOX-1-AT1/CHO細胞」という。)を使用した。
酸化LDLによる細胞反応の評価には、ルシフェラーゼアッセイを用いた。酸化LDLによってNFκBおよびSRFが活性化されることについては、当業者に良く知られている(例えば「Circulation Research. 2011; 108: 797-807, Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury」を参照のこと。)。ルシフェラーゼレポーターベクターpGF1-NFκBあるいはpGF1-SRF(いずれもSystem Biosciences社)と、pRL-CMV (Promega社)とを混合し、Lipofectamin LTX(invitrogen社)を用いて、LOX-1-AT1/CHO細胞に遺伝子導入した。遺伝子導入から16時間後、0.1%FBSおよび300ng/mlのdoxycyclineを含むF12培地に交換し、0.5%CO2条件下で24時間培養した。
図6によれば、LOX-1-AT1/CHO細胞において、酸化LDLによって惹起されるNFκBおよびSRFの活性化を、Del−1(10μg/mlおよび30μg/mlの濃度)は有意に阻害したことが分かる。このときBSAによる阻害は認められなかった。図6に示すデータは有意差検定(スチューデントのT検定)を行っており、危険率5%未満で有意差がある場合は図6中に「*」が付されており、危険率1%未満で有意差がある場合は図6中に「**」が付されている。
(方法)
(1)Del−1高発現マウスの作製
Del−1高発現マウス(「Del−1−Tgマウス」という。)は以下のようにして作製された。
24週齢のDel−1高発現マウス(「Del−1−Tgマウス」という。)および野生型マウスに、20週間、高脂肪食(商品名: Atherogenic Rodoent Diet (型番:D12336)、リサーチダイエット社)を自由摂取させた。これらのマウスを解剖し、各個体から大動脈を取り出してOil Red O染色液(和光純薬工業株式会社製)により大動脈中の脂質を染色した。具体的には以下の通りである。
結果を図7に示す。図7(a)および(b)は20週間、高脂肪食を自由摂取させた、24週齢の野生型マウス(図中「WT」で表す。)の大動脈基部の脂質染色像(Oil Red O染色像)である。また図7(c)および(d)は24週齢のDel−1過剰発現マウス(図中「Del−1−Tg」で表す。)の大動脈基部の脂質染色像(Oil Red O染色像)である。図7(a)−(d)中、陽性染色部位を矢印で示す。また図7(e)は、大動脈基部中に観察された脂質沈着面積を定量した結果を示すグラフである。
Claims (3)
- Del−1(Developmental endothelial locus-1)タンパク質を有効成分として含有することを特徴とする酸化LDL阻害剤。
- 上記Del−1タンパク質は、
(a)配列番号1に示されるアミノ酸配列からなるタンパク質、または、
(b)配列番号1に示されるアミノ酸配列において、1個もしくは数個のアミノ酸が置換、欠失、挿入、もしくは付加されたアミノ酸配列からなり、且つ酸化LDL阻害活性を有するタンパク質であることを特徴とする請求項1に記載の酸化LDL阻害剤。 - 請求項1または2に記載の酸化LDL阻害剤を含有することを特徴とする動脈硬化性疾患の治療または予防のための薬学的組成物。
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US5874562A (en) * | 1995-06-07 | 1999-02-23 | Progenitor, Inc. | Nucleic acid encoding developmentally-regulated endothelial cell locus-1 |
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US20040009940A1 (en) * | 2000-10-20 | 2004-01-15 | Coleman Michael E. | Gene delivery formulations and methods for treatment of ischemic conditions |
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