[Frontiers in Bioscience S3, 1216-1231, June 1, 2011]

Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood-brain barrier permeability

Yong Gu1, Cathleen Michelle Dee2, Jiangang Shen1, 3

1School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China, 2Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China, 3Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Roles of matrix metalloproteinase in regulating BBB permeability during cerebral ischemia-reperfusion injury
3.1. Tight junction proteins and basal lamina
3.2. Matrix metalloproteinases
4. Oxidative stress induces BBB leakage via activating MMPs pathway
4.1. ROS and BBB leakage
4.2. RNS and BBB leakage
4.2.1. NO and BBB leakage
4.2.2. Peroxynitrite and BBB leakage
5. Caveolin-1 regulates BBB permeability
5.1. Regulation of BBB permeability
5.2. Impacts on MMPs activation and secretion
5.3. Effects on tight junction proteins
6. Interaction between caveolin-1 and RNS
6.1. Cav-1 regulates NO production through binding with NOS
6.2. NO modulates caveolin-1 levels
7. Summary and perspective
8. Acknowledgements
9. References

1. ABSTRACT

Free radicals play an important role in cerebral ischemia-reperfusion injury. Accumulations of toxic free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) not only increase the susceptibility of brain tissue to ischemic damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death. Activating matrix metalloproteinases (MMPs) is a key step in BBB disruption. MMPs are proteolytic zinc-containing enzymes responsible for degradation of the extracellular matrix around cerebral blood vessels and neurons. Free radicals can activate MMPs and subsequently induce the degradations of tight junctions (TJs), leading to BBB breakdown in cerebral ischemia-reperfusion injury. Recent studies revealed that caveolin-1, a membrane integral protein located at caveolae, can prevent the degradation of TJ proteins and protect the BBB integrity by inhibiting RNS production and MMPs activity. The interaction of caveolin-1 and RNS forms a positive feedback loop which provides amplified impacts on BBB dysfunction during cerebral ischemia-reperfusion injury. Here, we reviewed the recent progress in the interactions of RNS, caveolin-1 and MMPs. Current evidence indicates that the interactions of RNS, caveolin-1 and MMPs are critical signal pathways in BBB disruption and infarction enlargement during cerebral ischemia-reperfusion injury.