Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury.
The roles of caveolin-1 (cav-1) in regulating blood-brain barrier (BBB) permeability are unclear yet. We previously reported that cav-1 was down-regulated and the production of nitric oxide (NO) induced the loss of cav-1 in focal cerebral ischemia and reperfusion injury. The present study aims to address whether the loss of cav-1 impacts on BBB permeability and matrix metalloproteinases (MMPs) activity during cerebral ischemia-reperfusion injury. We found that focal cerebral ischemia-reperfusion down-regulated the expression of cav-1 in isolated cortex microvessels, hippocampus, and cortex of ischemic brain. The down-regulation of cav-1 was correlated with the increased MMP-2 and -9 activities, decreased tight junction (TJ) protein zonula occludens (ZO)-1 expression and enhanced BBB permeability. Treatment of N(G) -nitro-L-arginine methyl ester [L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor] reserved the expression of cav-1, inhibited MMPs activity, and reduced BBB permeability. To elucidate the roles of cav-1 in regulating MMPs and BBB permeability, we used two approaches including cav-1 knockdown in cultured brain microvascular endothelial cells (BMECs) in vitro and cav-1 knockout (KO) mice in vivo. Cav-1 knockdown remarkably increased MMPs activity in BMECs. Meanwhile, with focal cerebral ischemia-reperfusion, cav-1 deficiency mice displayed higher MMPs activities and BBB permeability than wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability was partly reversed in cav-1 deficiency mice. These results, when taken together, suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in focal cerebral ischemia and reperfusion injury. The effects of L-NAME on MMPs activity and BBB permeability are partly mediated by preservation of cav-1.
School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Yong
Y
Gu
Guoqing
G
Zheng
Mingjing
M
Xu
Yue
Y
Li
Xingmiao
X
Chen
Wenzong
W
Zhu
Yao
Y
Tong
Sookja K
SK
Chung
Ke Jian
KJ
Liu
Jiangang
J
Shen
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology*; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology; D051242:Caveolin 1 / Q000502:physiology*; D004396:Coloring Agents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005070:Evans Blue; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology*
D051242:Caveolin 1; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D005070:Evans Blue; D052248:Nitric Oxide Synthase Type I; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019331:NG-Nitroarginine Methyl Ester