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プロテオミクスによる動脈硬化症及び石灰化大動脈弁疾患の病態制御関連因子解明

東 秀行 富山大学

2022.03.02

概要

心血管疾患は、生命危機や重篤な後遺症をもたらす疾患として世界的に認知されており、その罹患者数は年々増加の一途をたどっている。心血管疾患の一つであるアテローム性動脈硬化症では、プラークの形成及び破裂に伴う血流障害によって心血管イベントを発生させる。そのため、動脈硬化の予防には、プラークの予防や安定化を目的とした生体内脂質量を制御するスタチンの投与が第一選択とされている。また、心臓内の血流動態に支障をきたす石灰化大動脈弁疾患では、弁尖の肥厚や硬化が心血管イベント発生の起点となる病状であり、その治療法として外科的治療が適用されている。しかし、これら疾患の疾病率や死亡率は未だ高水準であることから、既存の薬物療法や外科的療法では本疾患の克服には至っていない。

近年の創薬研究において、心血管病変に関連した生体応答について、この発生に関わる分子的要因の同定と臨床での検証が進められている。これらを進める上で、疾患の表現型に直接寄与するタンパク質や翻訳後修飾を対象としたプロテオミクスの有用性が高い。質量分析装置を用いたプロテオミクスとして、タンパク質分解酵素によって生成されるペプチドを測定対象とし、ペプチドから全長のタンパク質情報を解析する手法が用いられている。心血管疾患において、病理的炎症応答と翻訳後修飾であるadenosine diphosphate(ADP)-リボシル化、また、心血管イベントとhigh density lipoprotein(HDL)との関係性が明らかにされてきており、これらの心血管疾患の病態制御における役割に関心が高まっている。また、大動脈弁の石灰化について、薬物療法の確立に向けた病態制御に関わる因子の同定が期待されている。しかし、従来のプロテオミクスではこれら翻訳後修飾や病態制御タンパク質の同定に必要とされる検出感度に達しておらず、これらを対象とするプロテオミクスの心血管疾患研究への活用は困難とされてきた。本研究では、翻訳後修飾や微量な疾患関連タンパク質の解析を実現可能とするプロテオミクスを構築し、動脈硬化症や石灰化大動脈弁疾患の病態進行や病態制御に関わる因子を解明することを目的とした。

1.ヒトマクロファージ様細胞(THP-1細胞)、マウス肝臓及び脾臓におけるADP-リボシル化タンパク質の網羅的解析1,2)
病理的炎症応答の抑制は、循環血液中脂質量に依存せず、再発性心血管イベントの発生率を低下させることが示されており、心血管疾患における炎症制御の重要性が高まっている。ADP-リボシル化は細胞応答を調節する翻訳後修飾であり、炎症性サイトカインであるinterferon-gamma(IFN-γ)刺激時には、マクロファージにおけるpoly-ADP-ribose polymerase(PARP)14の発現誘導及び抗炎症作用が示されている。そこで、IFN-γ刺激時にPARP14が炎症抑制作用を示す機序に迫るために、PARP14が高発現するマクロファージ、マウス肝臓及び脾臓を用いて、IFN-γ刺激によるADP-リボシル化タンパク質の変動を解析した。

翻訳後修飾タンパク質の微量性や構造複雑性などのために、一般的なプロテオミクスでは修飾タンパク質の検出は困難である。そこで、ヒトマクロファージ様細胞株であるTHP-1細胞由来のADPリボシル化ペプチド試料を用い、ADP-リボシル化ペプチドのデータ取得法及び解析法を検討した。データ取得では、ADP-リボシル化に特有な4種のフラグメントイオン、並びにhigh-energy collision dissociation(HCD)とelectron transfer/high-energy collision dissociation(EThcD)の2種の解離法を活用し、修飾ペプチドに対する選択性や同定した修飾ペプチド情報の信頼性を向上させた。さらに、データ取得にgas phase segmentationを適用し、ADP-リボシル化ペプチドに対する検出効率を向上させた。データ解析では、HCDはADP-リボシル化ペプチドのアミノ酸配列の同定に、また、EThcDは信頼性の高い修飾アミノ酸位置の同定に優位であることを明らかにした。

本手法を用いることで、THP-1細胞において、145種のADP-リボシル化タンパク質が同定され、IFN-γ刺激時にはリボソームやヒートショックタンパク質のADP-リボシル化が誘導されることを示した。さらに、THP-1細胞におけるPARP14自身のADP-リボシル化を検出し、IFN-γ刺激に応答してPARP14(D1604)のADP-リボシル化が亢進されることを見出した。また、IFN-γ刺激後の肝臓ではリボソームやヒートショックタンパク質、脾臓ではヘモグロビンやアルブミンタンパク質のADP-リボシル化が誘導されることを明らかにした。以上の結果から、マクロファージ、肝臓及び脾臓において、IFN-γ刺激に応答してPARP14はADP-リボシル化を促進し、そして炎症抑制に関連するシグナル伝達を担うことが示唆された。

2.HDL亜分画中コレステリルエステル転送蛋白(CETP)の代謝速度論的解析3)
循環血液中HDL-cholesterol(HDL-C)濃度は、心血管イベントの発症頻度と負の相関関係にあることが示されている。しかし、血液中HDL-C濃度上昇を作用機序とするCETP阻害薬について、臨床試験では動脈硬化症に対する有効性が認められていない。近年、HDLの機能を精査する研究として、HDLサイズ亜分画におけるHDL関連タンパク質の分布様式が示されており、CETPの分布様式に関し明らかにすることで、HDLによる病態制御機構の解明に繋がることが期待される。

血漿中には高発現タンパク質が多数存在し、かつCETPの血漿中存在量は非常に少ないことから、従来のHDL関連タンパク質の分布様式を明らかにしてきたプロテオミクスでは、CETPの代謝速度論的解析に必要なデータ取得は困難である。そこで、従来の質量分析装置と比べ高分解能を有するOrbitrap Fusion Lumosの有用性を検証し、本装置を用いた高分解能測定によってCETPの安定同位体標識トレーサーペプチドを検出可能とした。本手法を用いることで、CETPはα1に20%及びα2に70%と、HDLの中でも大きな亜分画に分布し、血漿中へ分泌後はこれら亜分画間を移行せずに消失することを示した。以上の結果から、脂質輸送タンパク質であるCETPについて、生体内ではHDL亜分画間のサイズ制御には寄与せず、亜分画のサイズ維持に関与することが示唆された。

3.ヒト石灰化大動脈弁におけるタンパク質の網羅的解析4,5)
大動脈弁は、弁の大動脈側のfibrosa層、中間のspongiosa層、そして左心室側のventricularis層の3層構造を有し、fibrosa層の根元付近が石灰化の発症部位となる。しかし、石灰化大動脈弁においては、弁尖の不均一な層構造、血漿由来の高発現タンパク質及びドナー間差などが障壁となり、弁組織全体を用いたプロテオミクスでは病態関連分子の同定に至っていない。そこで、弁の組織から細胞分画まで4種の大動脈弁由来試料を調製し、網羅的なタンパク質発現解析に用いた。

ヒト大動脈弁組織おけるプロテオミクスでは、不均一な層構造に起因する影響を軽減するために石灰化弁の病変部位及び各組織層から試料を採取した。石灰化弁の病変部位では、線維化部位にて筋線維形成や酸化ストレスに関連するタンパク質、石灰化部位にてalkalinephosphatase, tissue nonspecificisozyme(TNAP)などの石灰化に関連するタンパク質の発現増加が示された。石灰化弁の各組織層では、fibrosa層にてapolipoproteinBなどの炎症に関わる血漿タンパク質の発現増加が示され、弁の石灰化と炎症応答との関連性が示唆された。さらに、血漿由来の高発現タンパク質に起因する影響を軽減するために、弁組織の主な構成細胞である弁間質細胞を単離及び培養した。Fibrosa層由来とventricularis層由来の弁間質細胞とを比較した際に、fibrosa層由来細胞では石灰化誘導条件下において顕著な石灰化が観察された。石灰化を誘導したfibrosa層由来弁間質細胞では、弁組織において検出された石灰化関連タンパク質に加え、線維化に関わるfibronectin-1などの発現誘導が示された。最後に、ヒト初代培養弁間質細胞の石灰化能にドナー間差をもたらす因子としてTNAPを同定し、TNAPが発現しかつ石灰化誘導に感受性を示す弁間質細胞の細胞質及び核分画における網羅的な石灰化関連タンパク質情報を得た。以上の結果から、4種のヒト大動脈弁由来試料を用いたプロテオミクスによって、石灰化と炎症や線維化との関連性を示唆し、さらに、石灰化誘導時の網羅的なタンパク質発現や細胞内局在情報を明らかにした。

結論
動脈硬化症及び石灰化大動脈弁疾患における病態制御因子同定及びその機構解明に向けて、質量分析装置を基盤とするプロテオミクスを実施した。ADP-リボシル化タンパク質の網羅的同定を可能としたプロテオミクスでは、IFN-γ刺激時のマクロファージ、肝臓及び脾臓におけるPARP14関連ADP-リボシル化シグナルを示唆し、炎症応答におけるPARP14関連ADP-リボシル化シグナルを精査する研究が進展していくことで、PARP14による炎症抑制機構の解明に貢献することが期待される。CETPの安定同位体標識トレーサー検出を可能としたプロテオミクスでは、CETPのHDLサイズ亜分画における代謝様式を示し、生体内HDLの役割が明らかにされていくことによって、HDLによる病態制御に関わる因子の解明並びに適切な創薬標的の提示に繋がることが期待される。石灰化大動脈弁を用いたプロテオミクスでは、4種の弁組織由来試料を用いて、弁組織を対象とした解析で直面する課題を克服し、弁石灰化病態に関連する因子を見出した。本研究にて構築した手法並びに得られた知見は、創薬標的の同定に向けた病態制御因子の同定及び病態制御機構の解明に寄与し、そして心血管疾患における新医薬品の創出に繋がっていくものと考えられる。

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