JP2018507912A - Dpp−4の抑制剤を含む弁膜石灰化の予防または治療用の組成物 - Google Patents
Dpp−4の抑制剤を含む弁膜石灰化の予防または治療用の組成物 Download PDFInfo
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Abstract
Description
ヒト大動脈弁膜の標本は、ソウルアサン病院で大動脈弁膜の置換術を受けた正常患者とひどい石灰化の病変形成の患者から得た。各サンプルの半分は、直ちにRNAlater(ライフテクノロジー)に貯蔵して、残り半分のOCT化合物(さくらFinetek社)に固定させた。ヒト由来のサンプルの収集に対する研究プロトコルは、ソウルアサン病院(ソウル、韓国)の臨床試驗審査委員会(IRB)の承認を受けて進行した。
C57BL/6J起源のeNOS−/−(Endothelial nitric oxide synthase knock−out)マウス(8週齢,n=10,The Jackson Laboratory,Bar Harbor,Me,USA)と同種の野生対照群のマウス(8週齢、wild type、WT、n=10)を利用した。搬入後3ヵ月齢までには標準のげっ歯類の飼料を与えた。
実施例2でeNOS−/−マウスと野生型マウスで、心臓とともに摘出した大動脈を無血清(serum−free)M199(Cellgro)につけて洗った後、小片に切った後、M199に20%ウシ胎児血清(fetal calf serum)、3mg/mlコラゲナーゼ(Sigma)を添加し、37℃の水槽で3時間湯煎した。分離された細胞は抗SM単クローン抗体(Sigma)を使用して血管平滑筋細胞であることを確認した。分離された血管平滑筋細胞を30%濃度で分注して24時間後、骨形成培地(Osteogenic Basal Medium,Osteogenic SingleQuots,Lonza,USA)で交替した。培地は3日ごとに交替して28日間、培養した。
NO生合成の抑制剤であるL−NAME(Nω−Nitro−L−arginine methyl ester)を処理すると、大動脈でDPP−4の発現が顕著に増加することで示され、NOの欠乏がDPP−4の発現を引き起こすことで知られている。
[配列番号1]5’−CAGCCAGATAACATGCCACACCCAACCCCTTC−3’
[配列番号2]5’−GAAGGGGTTGGGTGTGGCATGTTATCTGGCTG−3’
大動脈弁膜の石灰化の過程でDPP−4が顕著に増加されることは弁膜の石灰化でDPP−4が潜在的な役割をしたということを意味する。これを証明するため、eNOS−/−マウスの大動脈石灰化に選択的のDPP−4の抑制剤であるシタグリプチン(sitagliptin)を処理し、その効果を確認した。
ヒト大動脈弁膜のVIC(Valve interstitial cell)は繊維芽細胞、筋芽細胞及び平滑筋細胞の異種細胞の集合であり、VSMCと類似した特徴を有して、造骨細胞の転移分化をすることができる。
シタグリプチン以外のDPP−4の抑制剤による弁膜石灰化の抑制効果を確認するために、様々な種類のDPP−4の抑制剤の処理によるeNOS−/−マウス由来のVSMC(Vascular Smooth Muscle Cell,VSMC)の骨細胞化(Osteogenic differentiation)の抑制効果を確認した。
Claims (7)
- DPP−4(Dipeptidyl peptidase−4)の抑制剤を含む弁膜石灰化の予防または治療用の医薬組成物。
- 前記DPP−4の抑制剤はDPP−4のヌクレオチドの発現またはDPP−4のタンパク質の活性を抑制することを特徴とする、請求項1に記載の弁膜石灰化の予防または治療用の医薬組成物。
- 前記DPP−4のヌクレオチドの発現を抑制することは、前記DPP−4のmRNAに対するアンチセンスヌクレオチド、アプタマー、低分子干渉RNA(siRNA)、低分子ヘアピン型RNA(shRNA)、マイクロRNA(miRNA)及びRNA干渉(RNAi)から成る群より選択されることを特徴とする、請求項2に記載の弁膜石灰化の予防または治療用の医薬組成物。
- 前記DPP−4タンパク質の活性を抑制するものは、DPP−4に対する抗体、シタグリプチン(sitagliptin)、ビルダグリプチン(vildagliptin)、サキサグリプチン(saxagliptin)、リナグリプチン(linagliptin)、デュトグリプチン(dutogliptin)、ジェミグリプチン(gemigliptin)、アログリプチン(alogliptin)、アナグリプチン(anagliptin)、エボグリプチン(evogliptin)、ベルベリン(Berberine)、ディプロチン(Diprotin)及びルペオール(Lupeol)から成る群より選択されることを特徴とする、請求項2に記載の弁膜石灰化の予防または治療用の医薬組成物。
- 前記弁膜石灰化は、弁膜症、高脂血症、老化、エストロゲン欠乏症、狭心症、心不全、腎臓疾患、尿毒症、糖尿病、炎症疾患及び心血管疾患から成る群より選択されることを特徴とする、請求項1に記載の弁膜石灰化の予防または治療用の医薬組成物。
- 前記弁膜石灰化は、大動脈弁膜の石灰化であることを特徴とする、請求項1に記載の弁膜石灰化の予防または治療用の医薬組成物。
- DPP−4(Dipeptidyl peptidase−4)の抑制剤を含む弁膜石灰化の予防または改善用の食品組成物。
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CN109593726A (zh) * | 2018-12-26 | 2019-04-09 | 重庆精准生物技术有限公司 | 增强car-t细胞归巢到实体肿瘤组织能力的试剂及其应用 |
CN111321107A (zh) * | 2019-02-01 | 2020-06-23 | 南方医科大学南方医院 | 人主动脉瓣膜间质细胞的分离及培养方法 |
WO2021080396A1 (ko) * | 2019-10-24 | 2021-04-29 | 가톨릭대학교 산학협력단 | Rspo3 억제제를 포함하는 심장 판막 질환의 예방 또는 치료용 조성물 |
CN111012772B (zh) * | 2020-01-06 | 2023-06-02 | 华中科技大学同济医学院附属协和医院 | 咖啡酸苯乙酯在治疗主动脉瓣膜钙化病中的用途 |
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