Limb ischemic perconditioning attenuates blood-brain barrier disruption by inhibiting activity of MMP-9 and occludin degradation after focal cerebral ischemia

Changhong Ren, Ning Li, Brian Wang, Yong Yang, Jinhuan Gao, Sijie Li, Yuchuan Ding, Kunlin Jin, Xunming Ji

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.

Original languageEnglish
Pages (from-to)406-417
Number of pages12
JournalAging and Disease
Volume6
Issue number6
DOIs
StatePublished - 1 Jan 2015

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Occludin
Middle Cerebral Artery Infarction
Brain Ischemia
Blood-Brain Barrier
Matrix Metalloproteinases
Tight Junction Proteins
Extremities
Claudin-5
Brain Edema
Endothelial Cells
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Matrix Metalloproteinase 9
Neuroprotective Agents
Proteolysis
Fluorescent Antibody Technique
Sprague Dawley Rats
Western Blotting
Stroke
Staining and Labeling

Keywords

  • Blood-brain barrier
  • Ischemic stroke
  • Matrix metalloproteinases
  • Remote ischemic perconditioning
  • Tight junction

Cite this

Ren, Changhong ; Li, Ning ; Wang, Brian ; Yang, Yong ; Gao, Jinhuan ; Li, Sijie ; Ding, Yuchuan ; Jin, Kunlin ; Ji, Xunming. / Limb ischemic perconditioning attenuates blood-brain barrier disruption by inhibiting activity of MMP-9 and occludin degradation after focal cerebral ischemia. In: Aging and Disease. 2015 ; Vol. 6, No. 6. pp. 406-417.
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Limb ischemic perconditioning attenuates blood-brain barrier disruption by inhibiting activity of MMP-9 and occludin degradation after focal cerebral ischemia. / Ren, Changhong; Li, Ning; Wang, Brian; Yang, Yong; Gao, Jinhuan; Li, Sijie; Ding, Yuchuan; Jin, Kunlin; Ji, Xunming.

In: Aging and Disease, Vol. 6, No. 6, 01.01.2015, p. 406-417.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Limb ischemic perconditioning attenuates blood-brain barrier disruption by inhibiting activity of MMP-9 and occludin degradation after focal cerebral ischemia

AU - Ren, Changhong

AU - Li, Ning

AU - Wang, Brian

AU - Yang, Yong

AU - Gao, Jinhuan

AU - Li, Sijie

AU - Ding, Yuchuan

AU - Jin, Kunlin

AU - Ji, Xunming

PY - 2015/1/1

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N2 - Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.

AB - Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.

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