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低出力パルス波超音波治療(LIPUS)は肺高血圧症マウスの右心機能を改善する-新たな非薬物治療法としての可能性-

中田 貴史 東北大学

2022.03.25

概要

【背景】右心不全は肺動脈性肺高血圧症(PAH)患者の重要な予後規定因子であるが、有効な治療法は未だ確立されていない。我々はこれまでに、低出力パルス波超音波(LIPUS)が、内皮型一酸化窒素合成酵素(eNOS)の活性化を介した微小循環の改善により、左心不全動物モデルの心機能を改善することを示してきた。

【目的】本研究では、2 つの右心不全動物モデルを使用し、eNOS の機能不全が右心不全に関与しているかどうか、また、LIPUS 治療が右心不全を改善するかどうかを検討した。

【方法と結果】右室圧負荷による右心不全モデルとして野生型および eNOS 遺伝子欠損(eNOS-/-)マウスの肺動脈縮窄(Pulmonary artery banding;PAB)モデルを使用し、 PAH による右心不全モデルとして Sugen/hypoxia(SU/Hx)ラットを使用した。野生型マウスに対して PAB を行ったところ、右室での eNOS 活性が有意に低下しており、 eNOS-/-マウスでは野生型マウスに比べて PAB 後の右心不全が有意に増悪していた。プラセボ治療と比較して、LIPUS 治療は eNOS とその下流のシグナル(可溶性グアニル酸シクラーゼ、プロテインキナーゼ G など)の活性化を介して、PAB マウスの右心機能障害を有意に改善させたが、eNOS-/-マウスではLIPUS 治療の有効性は消失した。 SU/Hx ラットでも、LIPUS 治療はプラセボ治療と比較し右心機能障害を改善させた。さらに、SU/Hx ラットの RV から採取した心筋組織(trabeculae)を用いて電気刺激による収縮下での発生張力と細胞内 Ca2+濃度([Ca2+] i)を測定した。LIPUS 治療群では、プラセボ群と比較し最大収縮速度(dF/dt max)、最大弛緩速度(dF/dt min)の有意な増加と、[Ca2+] i の減衰時間の有意な短縮が認められ、LIPUS 治療は組織レベルでも心筋の収縮/弛緩特性を改善させることが示唆された。右室における蛋白発現の解析では、LIPUS 治療により SU/Hx ラットの右室における Ca2+ハンドリング関連タンパク質(SERCA2、ホスホランバン)の発現が亢進した。組織学的には、LIPUS 治療により両モデルにおいて心筋細胞の肥大と心筋間質の線維化の改善が認められた。

【結論】 以上の結果から、eNOS が右心不全の病態生理において重要な役割を果たしていることが明らかになった。LIPUS 治療は eNOS-NO-cGMP-PKG 経路の活性化を介して右心不全を改善させうることが示唆された。

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