JP2007505628A - 心収縮能及び心不全傾向の調節 - Google Patents
心収縮能及び心不全傾向の調節 Download PDFInfo
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Abstract
Description
(政府補助金情報)
本発明は、NIH助成金(NIH Grant)番号HL62927、HL26057、及びHL64018に基づく政府支援を受けて実施された。米国政府は、本発明に一定の権利を有する。
実施例1.トランスジェニックマウスの作製
胚幹細胞における標準の相同的組み換えによって、PKCα遺伝子を欠損の標的とし、続いてキメラマウスを作り出し、それを繁殖させ、標的対立遺伝子を取り出して生殖細胞系列に移した。PKCα中のATP結合カセットをコードするエクソンを欠損させて、タンパク質発現に関するヌル対立遺伝子を得た。PKCα過剰発現トランスジェニックマウスの作製のために、PKCαをコードするcDNAをネズミα−ミオシン重鎖プロモーター含有発現ベクターへとサブクローン化し、新しい受精卵母細胞に注入した。MLP、PP1c、及び圧力過負荷外科モデル(TAC)は、すべて別記した(アーバー(Arber)ら(1997)細胞(Cell)88:393〜403、カール(Carr)ら(2002)分子細胞生物学(Mol.Cell.Biol.)22:4124〜4135、及びリャン(Liang)ら(2003)EMBO.J.22:5079〜5089)。一貫性のために、すべての研究でオスだけを使用した。すべての動物実験は、所内動物実験委員会(Institutional Animal Care and Use Committee)の承認を受けた。
すべての遺伝子型又は治療群からのマウスをイソフルランで麻酔し、15−MHZマイクロプローブを備えたヒューレットパッカード5500(Hewlett Packard 5500)機器を使用して心エコーを実施した。各群につき別個の4匹のマウスから3回ずつMモードで心エコー測定値を取得した。本研究で使用される単離された摘出マウス心臓標本については、これまでに詳細に記載されており(ギューリック(Gulick)ら(1997)循環研究(Circ.Res.)80:655〜664)、ここで使用した閉胸式機能心臓モデルと同様である(ローレンツ(Lorenz)ら(1997)米国生理学雑誌(Am.J.Physiol.)272:H1137〜H1146)。
心臓を、指示した時点で採取し、10%ホルマリン−PBS溶液中で固定し、パラフィンに包埋した。各群からの連続5μm心臓切片を分析した。試料を、ヘマトキシリン・エオジン染色又はマッソン(Masson)のトリクローム染色で染色した。肥大分子マーカの心臓での遺伝子発現を、これまでに記載されているように、RNAドットブロット分析によって評価した(ジョーンズ(Jones)ら(1996)臨床研究雑誌(J.Clin.Invest)98:1906〜1917)。
スプラーグ・ドーリー(Sprague-Dawley)ラット心臓から心室筋細胞を単離し(ウェストフォール(Westfall)ら(1997細胞生物学諸法(1997 Methods Cell Biology)52:307〜322)、5%血清を含むDMEM中でラミニンコーティングされたカバースリップ上で2時間平板培養した。次いで、培地を、組み換えウイルスベクターを含有する無血清DMEMに取り替えた。1時間後に無血清DMEMを添加し、培地を2日ごとに交換した。単離細胞の約70〜85%が棒状であり、心臓当たり1〜2×106の棒状筋細胞がある。短縮アッセイに使用する筋細胞を、ペニシリン/ストレプトマイシン、10mMヘペス(Hepes)、0.2mg/mLアルブミン、及び10mMグルタチオンが追加された培地199内で電気的に刺激した(ウェストフォール(Westfall)及びボートン(Borton)(2003)生物化学雑誌(J.Biol.Chem.)278:33694〜33700)。培養の1日後、筋細胞を、白金電極を備えた刺激チャンバに移動し、筋細胞の25%未満に攣縮を生み出す電圧で0.2Hzにおいて2.5ms刺激した。刺激チャンバ内の培地は、12時間ごとに取り替えた。収縮機能の研究では、カバースリップを、サルコメア短縮測定のためのM199を含有する熱制御チャンバ内に設置した。サルコメア長を、可変視野率CCDビデオカメラ(アイオンオプティクス(Ionoptix)、マサチューセッツ州ミルトン(Milton))によって測定し、サルコメア長検出ソフトウェアで記録した。筋細胞を0.2Hzで刺激し、サルコメア短縮を60秒間記録した。ピーク短縮、ピークまでの時間、最大弛緩の半分までの時間、並びに収縮及び弛緩速度の測定値を、10回の収縮についての信号平均から得た。これらの研究の結果を、一元配置分散分析及びポストホック・ニューマンクールズ(post-hoc Newman-Keuls)試験によって比較した。
3月齢の野生型又は非トランスジェニック(Ntg)マウス及びPKCα−KOマウスの心室から心筋細胞を分離し、これまでに記載されているように、電気生理学的記録を実施した(ペトラシェフスカヤ(Petrashevskaya)ら(2002)心臓血管研究(Cardiovasc.Res.)54:117〜132、及びマサキ(Masaki)ら(1997)米国生理学雑誌(Am.J.Physiol.)272:H606〜H612)。簡潔には、心臓に、逆行性冠動脈潅流を、無Ca2+タイロード溶液によって10分間実施し、コラゲナーゼタイプII(ワージントン(Worthington)、1.0mg/ml)を含有する、5mMタウリン及び10mMのBDM(2,3−ブタン、ジオン−モノキサミン(monoxamine))が追加されたタイロード溶液(250μMのCa2+)で、95%O2及び5%CO2を吹き込みながら37℃で8〜12分間実施した。潅流後、心臓を取り出し、心室組織を低Cl-・高K+−KB培地中で機械的に細かく切断した。次いで、細かく切断された心室組織を、静かに濾過し、電気生理学的研究まで4℃で保管した。実験には、明確な横紋をもち、自発収縮又は顕著な肉芽形成(granulation)のない、Ca2+耐性細胞だけを選択した。
カルシウム・トランジェント測定の評価のためのマウス左心室筋細胞の単離を、これまでに記載されているように実施した(チュー(Chu)ら(1996)循環研究(Circ.Res.)79:1064〜1076)。Ca2+トランジェントは、室温で心筋細胞から測定した。簡潔には、麻酔をかけた(ペントバルビタールナトリウム、70mg/kg、腹腔内投与(i.p.))成体マウスから、マウス心臓を摘出し、ランゲンドルフ潅流装置内に設置し、37℃において無Ca2+タイロード溶液で3分間潅流した。標準タイロード溶液は、140mMのNaCl、4mMのKCl、1mMのMgCl2、10mMのグルコース、及び5mMのHEPESを含有し、pH7.4であった。次いで、潅流を、75単位/mLのタイプ1コラゲナーゼ(ワージントン(Worthington))を含有する同一の溶液に切り替えて、心臓が弛緩状態になるまで潅流を続けた(約10〜15分)。左心室組織を摘出し、細かく切断し、ピペット分離し、240μmスクリーンに通して濾した。次いで、細胞懸濁液を、順に、25、100、200μM、及び1mMのCa2+−タイロード中で洗浄した。細胞内Ca2+シグナルを得るために、細胞をfura−2(Fura−2/AM、2μM)のアセトキシメチルエステル形態によって室温で30分間インキュベートし、1.8mMのCa2+−タイロード溶液に再懸濁させた。筋細胞懸濁液をプレキシグラスチャンバ内に入れ、それを倒立エピ蛍光顕微鏡(ニコン・ダイアフォト200(Nikon Diaphot 200))のステージ上に位置決めし、1.8mMのCa2+−タイロード溶液によって室温(22℃〜23℃)で潅流した。筋細胞収縮を、グラスS5刺激装置(Grass S5 stimulator)(0.5Hz、方形波)によってフィールド刺激し、細胞を、デルタスキャン・デュアルビーム分光蛍光光度計(Delta Scan dual-beam spectrophotofluorometer)(フォトン・テクノロジー・インターナショナル(Photon Technology International))によって340及び380nm5で交互に興奮させた。Ca2+トランジェントを、得られる510nm発光の340/380nm比として記録した。340/380nm比並びにCa2+シグナルが80%減衰する時間及びτによって推定される、ベースライン及び振幅を獲得した。すべてのデータは、フェリックス(FeliX)及びアイオンウィザード(Ionwizard)からのソフトウェアを使用して分析された。
PKCキナーゼ反応混合物には、10μMの阻害物質−1、20mMのMOPS、pH7.2、25mMのβ−グリセロールホスフェート、1mMのMgCl2、1mMのオルトバナジウム酸ナトリウム、1mMのDTT、1mMのCaCl2、0.1mg/mLのホスファチジルセリン、0.01mg/mLジアシルグリセロール、100μMのATP、及び0.6mCi/mL[32P]ATPが含まれた。PKCをウサギ心筋から単離し(ウジェット(Woodgett)及びハンター(Hunter)(1987)生物化学雑誌(J.Biol.Chem.)262:4836〜4843)、組み換え野生型及びSer−67−Ala阻害物質−1を大腸菌から単離した(ビブ(Bibb)ら(2001)生物化学雑誌(J.Biol.Chem.)276:14490〜14497)。30℃で反応させ、特定の時点でアリコートを採取し、タンパク質試料緩衝剤の添加によって停止させた。SDS−PAGE及び放射能の直接定量によって化学量論(stoichiometries)を決定した。
これまでに記載されているように、日齢1〜2日のスプラーグ・ドーリー(Sprague-Dawley)ラット新生仔の酵素分離によって、新生仔ラット心筋細胞の初代培養を得た(デ・ウィント(De Windt)ら(2000)生物化学雑誌(J.Biol.Chem.)275:13571〜13579)。心筋細胞を、無血清条件下で、ペニシリン/ストレプトマイシン(100U/mL)及びL−グルタミン(2mmol/L)が追加されたM199培地で培養した。
心筋細胞におけるPKCαのアデノウイルスコード野生型又はドミナントネガティブ変異体の特性評価については、既に記載されている(ブラス(Braz)ら(2002)細胞生物学雑誌(J.Cell Biol.)156:905〜919)。ドミナントネガティブPKCα cDNAは、アミノ酸位置368でのATP結合ドメインにおけるリシンからアルギニンへの突然変異から成っていた。各組み換えアデノウイルスを、プラーク単離し、拡張させ、HEK293細胞中で力価試験を行った。典型的な実験は、37℃の加湿6%CO2インキュベータ内で2時間にわたって、100プラーク形成単位のmoiで6個の新生仔ラット心筋細胞を感染させるものであった。続いて、分析前に細胞をさらに24時間にわたって無血清M199培地で培養した。これらの条件下では、細胞の95%が組み換えタンパク質の発現を示した。
可溶性画分及び顆粒画分を、これまでに記載されているように調製した(ブラス(Braz)ら(2002)細胞生物学雑誌(J.Cell Biol.)156:905〜919)。タンパク質試料を、SDS−PAGE(10%ゲル)に供し、ハイボンド−P膜(Hybond-P membrane)(アマシャム・ファルマシア・バイオテク(Amersham Pharmacia Biotech))に移動し、7%ミルク中でブロッキングし、PKCα、β、δ、ε、SERCA2、カルセケストリン、PLB、ホスホ−セリン−16PLB、阻害物質−1、及びPP1cαに対する一次抗体でインキュベートした。ホスホ特異的I−1抗体については、既に記載されている(ビブ(Bibb)ら(2001)生物化学雑誌(J.Biol.Chem.)276:14490〜14497)。一次抗体を、3%ミルク中で4℃で一晩インキュベートした。二次抗体IgG(アルカリホスファターゼが結合した抗マウス、抗ウサギ、又は抗ヤギ)を、0.5〜3%ミルク中で室温で1時間インキュベートした。化学蛍光検出を、ビストラECF試薬(Vistra ECF reagent)(RPN5785、アマシャム・ファルマシア・バイオテク(Amersham Pharmacia Biotech))によって直接実施して、ホスファーイメージャー(PhosphorImager)で走査し、又はECL(アマシャム・ファルマシア・バイオテク(Amersham Pharmacia Biotech))によって化学発光を実施し、フィルム上で露光させた。
β−ガラクトシダーゼ、I−1、PKCα、及びPKCα−dnをコードするアデノウイルスで感染させた心筋細胞から、タンパク質抽出物を生成した。抽出物を、アガロースビーズに結合したPPIcαで免疫沈降させ、続いてI−1に対してウエスタンブロッティングを実施した。リン酸化タンパク質基質の調製及びタンパク質ホスファターゼの放射能アッセイは、タンパク質セリン/トレオニンホスファターゼ(PSP:Protein Serine/Threonine Phosphatase)アッセイシステム(ニューイングランド・バイオラボ社(New England BioLabs,Inc.))の指示通りに調製した。
カフェイン誘発性カルシウム・トランジェントを、4匹のPKCαヌルマウス由来の合計37個の筋細胞、及び3匹の野生型マウス由来の19個の対照筋細胞で測定した。コラゲナーゼ消化後、筋細胞にIndo−1AM(25μg/2mL)を室温で12分間負荷した。細胞内カルシウム・トランジェント(Indo−1蛍光比によって測定される)を、20mMカフェイン添加前及び添加中に、休止状態(電気刺激なし)で記録した。
4匹の野生型マウス及び4匹のPKCα−/−(PKCαヌル)トランスジェニックマウスから心臓を単離した。単離した心臓に、8×10-11〜8×10-7Mにわたる異なる9つの濃度でPMAを注入した。各濃度の即時PMA注入は、7分間実施された。収縮期及び拡張期それぞれにおける最大及び最小dP/dtについて心臓を測定した。そのような実験の1つで得られた結果を図36に示す。
標準曲線を使用して、健康なヒトの心臓におけるPKCアイソザイムの相対存在量を評価した。バクテリア内で生成された組み換えヒトタンパク質PKCα、PKCβI、PKCβII、PKCγ、及びPKCεを、民間業者から購入した。既知の濃度の3つのアリコートを調製した。
エクスビボ機能心臓標本を使用して即時PKCα阻害が心機能及び収縮性に及ぼす影響を直接調べる手段として、比較的選択性のあるPKCα/β阻害化合物であるRo−32−0432[2−{8−[(ジメチルアミノ)メチル]−6,7,8,9−テトラヒドロピリド[1,2−a]インドール−3−イル}−3−(1−メチルインドール−3−イル)マレイミド、HCl塩][3−{8−[(ジメチルアミノ)メチル]−6,7,8,9−テトラヒドロピリド[1,2−a]インドール−10−イル}−4−(1−メチルインドール−3−イル)−1H−ピロール−2,5−ジオン、HCl塩]を使用した。機能心臓標本は、心臓の固有のポンプ機能と、インビボで薬物が注入された場合に起こり得るような全血管抵抗の考えられる変化とを切り離す。
PKCαをコードするヌクレオチド配列を、緑色蛍光タンパク質(GFP)をコードするヌクレオチド配列に作用可能に結合させることによって、PKCα指標を調製した。PKCα−GFPヌクレオチド配列を含む発現カセットを調製した。PKCα−GFP発現カセットを含むアデノウイルスを調製した。
選択されたPKCα阻害物質を、心収縮能及び血行動態に及ぼす影響について、ナイーブラット及び心筋梗塞(MI)ラットの両方で評価する。
このアッセイは、様々な心筋症表現型に使用することができる。注目のPKCαヌクレオチド配列を、心臓組織に選択性のあるプロモーターを含有する発現ベクターへとクローニングする。注目のヌクレオチド配列に作用可能に結合した、プロモーターを含む発現カセットを、制限酵素で消化する。制限反応生成物を、アガロースゲル上で電気泳動し、発現カセットをアガロースから精製する。発現カセットを、当業者に既知の方法に従ってマイクロインジェクション用に調製する。発現カセットを使用してトランスジェニックマウスを提供する。トランス遺伝子の存在を、サザンブロット分析を使用して確認する。
以下の諸図では、特に指示のない限り、データを平均値の標準誤差とともに示す。
Claims (16)
- 少なくとも1つの細胞のゲノム内に少なくとも1つの安定に組み込まれた発現カセットを含むトランスジェニックマウスであって、前記発現カセットは、
(a)配列番号:1のヌクレオチド配列と、
(b)配列番号:1のヌクレオチド配列に対して少なくとも約90%の同一性を有するヌクレオチド配列と、
(c)配列番号:2のアミノ酸配列を有するポリペプチドをコードするヌクレオチド配列と、
(d)配列番号:2に記載のアミノ酸配列に対して少なくとも約90%の同一性を有するポリペプチドをコードするヌクレオチド配列と、
(e)配列番号:1に記載のヌクレオチド配列の少なくとも約50の連続ヌクレオチドを含むヌクレオチド配列と、
(f)厳密な条件下で配列番号:1に記載のヌクレオチド配列にハイブリダイズするヌクレオチド配列と、
(g)配列番号:7に記載のヌクレオチド配列と、
(h)(a)、(b)、(c)、(d)、(e)、又は(g)のヌクレオチド配列のいずれか1つの相補体から成るヌクレオチド配列と、
から成る群から選択される注目のヌクレオチド配列に作用可能に結合した、心臓組織に選択性のある調節配列を含む、トランスジェニックマウス。 - 心臓組織に選択性のある調節配列を含む発現カセットは、配列番号:1のヌクレオチド配列に作用可能に結合されている、請求項1に記載のトランスジェニックマウス。
- 心収縮能を調節する化合物を同定する方法であって、
(a)化合物をプロテインキナーゼC−αタンパク質と接触させる工程と、
(b)該化合物がプロテインキナーゼC−αに結合するかどうかを決定する工程と、
(c)プロテインキナーゼC−αに結合する化合物を心収縮能の調節剤として同定する工程とを含む方法。 - 心筋症を調節する化合物を同定する方法であって、
(a)化合物をプロテインキナーゼC−αタンパク質と接触させる工程と、
(b)該化合物がプロテインキナーゼC−αに結合するかどうかを決定する工程と、
(c)プロテインキナーゼC−αに結合する化合物を心筋症の調節剤としての化合物として同定する工程とを含む方法。 - プロテインキナーゼC−αタンパク質は、細胞内で発現され、調節剤の効果は、化合物に接触していない細胞と比較したときのプロテインキナーゼC−α活性の変化として測定される、請求項3又は4に記載の方法。
- (a)プロテインキナーゼC−αタンパク質の活性を調節する化合物を選択し、さらに、それらの化合物が心収縮能モデル系において心収縮能を調節するかどうかを決定する工程と、
(b)心収縮能モデル系において心収縮能を調節する試験化合物を、心収縮能を調節する候補化合物として同定する工程とをさらに含む、請求項3又は5に記載の方法。 - (a)プロテインキナーゼC−αタンパク質の活性を調節する化合物を選択し、さらに、それらの化合物が心筋症モデル系において心筋症を調節するかどうかを決定する工程と、
(b)心筋症モデル系において心筋症を調節する試験化合物を、心筋症を調節する候補化合物として同定する工程とをさらに含む、請求項4又は5に記載の方法。 - 請求項5、6、又は7のいずれかに記載の方法におけるモデル系としての、請求項1若しくは2に記載のトランスジェニックマウス又はそれらの細胞若しくは組織の使用。
- 少なくとも1つの細胞のゲノム内に少なくとも1つの切断プロテインキナーゼC−α遺伝子を含むトランスジェニックマウスであって、該切断は、プロテインキナーゼC−α発現レベルを低下させるのに十分である、トランスジェニックマウス。
- 哺乳類において心収縮能によって調節される疾患を治療又は予防する薬剤を製造する際の、プロテインキナーゼC−α調節化合物の使用。
- 哺乳類において心筋症を治療又は予防する薬剤を製造する際の、プロテインキナーゼC−α調節化合物の使用。
- 急性心不全の治療又は予防を必要とする哺乳類において急性心不全を治療又は予防する薬剤を製造する際の、プロテインキナーゼC−α調節化合物の使用。
- 請求項10、11、又は12のいずれかに記載のプロテインキナーゼC−α調節化合物の使用であって、該プロテインキナーゼC−α調節化合物は、Ro−32−0432、LY333531、及びRo−31−8220から成る群から選択されるプロテインキナーゼC−α阻害物質である、使用。
- 心収縮能によって調節される疾患の治療又は予防を必要とする哺乳類において、該疾患を治療又は予防する方法であって、
(a)心収縮能によって調節される疾患の治療又は予防を必要とする動物を識別する工程と、
(b)プロテインキナーゼC−α調節化合物を前記哺乳類に投与する工程とを含む方法。 - 心筋症の治療又は予防を必要とする哺乳類において心筋症を治療又は予防する方法であって、
(a)心筋症の治療又は予防を必要とする動物を識別する工程と、
(b)プロテインキナーゼC−α調節化合物を前記哺乳類に投与する工程とを含む方法。 - 急性心不全の治療又は予防を必要とする哺乳類において急性心不全を治療又は予防する方法であって、
(a)急性心不全の治療又は予防を必要とする動物を識別する工程と、
(b)プロテインキナーゼC−α調節化合物を前記哺乳類に投与する工程とを含む方法。
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