徳島大学 教育・研究者情報データベース(EDB)

1. (英) Nishimoto Sachiko

   役割	任意
   貢献度	任意
   学籍番号	推奨

2. (英) Aini Kunduziayi

   役割	任意
   貢献度	任意
   学籍番号	推奨

3. 福田 大受

   役割	任意
   貢献度	任意
   学籍番号	推奨

4. (英) Higashikuni Yasutomi

   役割	任意
   貢献度	任意
   学籍番号	推奨

5. (英) Tanaka Kimie

   役割	任意
   貢献度	任意
   学籍番号	推奨

6. (英) Hirata Yoichiro

   役割	任意
   貢献度	任意
   学籍番号	推奨

7. 八木 秀介([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.地域・家庭医療学])

   役割	任意
   貢献度	任意
   学籍番号	推奨

8. 楠瀬 賢也

   役割	任意
   貢献度	任意
   学籍番号	推奨

9. 山田 博胤([徳島大学.大学院医歯薬学研究部.医学域.連携研究部門(医学域).寄附講座系(医学域).地域循環器内科学])

   役割	任意
   貢献度	任意
   学籍番号	推奨

10. 添木 武([徳島大学.大学院医歯薬学研究部.医学域.連携研究部門(医学域).寄附講座系(医学域).実践地域診療・医科学])

    役割	任意
    貢献度	任意
    学籍番号	推奨

11. 島袋 充生

    役割	任意
    貢献度	任意
    学籍番号	推奨

12. 佐田 政隆([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.循環器内科学])

    役割	任意
    貢献度	任意
    学籍番号	推奨

(英) Activation of Toll-Like Receptor 9 Impairs Blood Flow Recovery After Hind-Limb Ischemia

(英) Peripheral artery disease causes significant functional disability and results in impaired quality of life. Ischemic tissue injury releases various endogenous ligands for Toll-like receptors (TLRs), suggesting the involvement of TLRs in blood flow recovery. However, the role of TLR9, which was originally known as a sensor for bacterial DNA, remains unknown. This study investigated the role of TLR9 in blood flow recovery in the ischemic limb using a mouse hind-limb ischemia model. Unilateral femoral artery ligation was performed in TLR9-deficient () mice and wild-type mice. In wild-type mice, femoral artery ligation significantly increased mRNA expression of TLR9 in the ischemic limb ( < 0.001) and plasma levels of cell-free DNA (cfDNA) as determined by single-stranded DNA (ssDNA) ( < 0.05) and double-stranded DNA (dsDNA) ( < 0.01), which are endogenous ligands for TLR9, compared with the sham-operated group. Laser Doppler perfusion imaging demonstrated significantly improved ratio of blood flow in the ischemic to non-ischemic limb in mice compared with wild-type mice at 2 weeks after ligation ( < 0.05). mice showed increased capillary density and reduced macrophage infiltration in ischemic limb. Genetic deletion of TLR9 reduced the expression of TNF-α, and attenuated NF-κB activation in ischemic muscle compared with wild-type mice ( < 0.05, respectively) at 3 days after the surgery. ODN1826, a synthetic agonistic oligonucleotide for TLR9, or plasma obtained from mice with ischemic muscle promoted the expression of TNF-α in wild-type macrophages ( < 0.05), but not in macrophages. ODN1826 also activated NF-κB signaling as determined by the degradation of IκBα in wild-type macrophages ( < 0.05), but not in macrophages. In vitro experiments using human umbilical vein endothelial cells demonstrated that TNF-α, or conditioned medium obtained from wild-type macrophages treated with ODN1826 accelerated cell death as determined by MTS assay ( < 0.05 and < 0.01, respectively). Our results suggest that ischemic muscle releases cfDNA, which activates TLR9 and enhances inflammation, leading to impairment of blood flow recovery in the ischemic limb. cfDNA-TLR9 signaling may serve as a potential therapeutic target in ischemic limb disease.

1. (英) Article.ELocationID: 10.3389/fcvm.2018.00144

2. (英) Article.PublicationTypeList.PublicationType: Journal Article

3. (英) KeywordList.Keyword: Toll-like receptor 9

4. (英) KeywordList.Keyword: blood flow recovery

5. (英) KeywordList.Keyword: hind-limb ischemia

6. (英) KeywordList.Keyword: inflammation

7. (英) KeywordList.Keyword: macrophage