Increased cerebral matrix metalloprotease-9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke

被引:65
作者
Kumari, Rashmi [1 ]
Willing, Lisa B. [1 ]
Patel, Shyama D. [1 ]
Baskerville, Karen A. [2 ]
Simpson, Ian A. [1 ]
机构
[1] Penn State Univ, Milton S Hershey Med Ctr, Dept Neural & Behav Sci, Coll Med, Hershey, PA 17033 USA
[2] Lincoln Univ, Dept Biol, Chester, PA USA
基金
美国国家卫生研究院;
关键词
blood-brain barrier; metalloproteases; neutrophil; stroke; tissue inhibitors of metalloproteases; type; 2; diabetes; BLOOD-BRAIN-BARRIER; HYPOXIA-ISCHEMIA; FOCAL ISCHEMIA; HEMORRHAGIC TRANSFORMATION; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; TISSUE INHIBITOR; NEURONAL DEATH; GENE KNOCKOUT; UP-REGULATION;
D O I
10.1111/j.1471-4159.2011.07487.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Diabetes is a major risk factor of stroke and is associated with increased frequency of stroke and a poorer prognosis for recovery. In earlier studies we have utilized type 2 diabetic mouse models of stroke and demonstrated that diabetic db/db and ob/ob mice experience larger infarct volumes and impaired recovery associated with greater infiltration of macrophage following hypoxic-ischemic (H/I) insult than their heterozygous non-diabetic db/+ and ob/+ littermates. To obtain a better understanding of the pathogenesis of the impaired recovery, we have investigated the role of matrix metalloproteases and their endogenous inhibitors in the breakdown of the bloodbrain barrier (BBB) following H/I. Diabetic db/db mice showed a significant and more rapid increase in matrix metalloprotease (MMP)-9 mRNA, protein and gelatinolytic activity compared with db/+, which resulted in an increased degradation of occludin and collagen IV and subsequently, an increased BBB permeability and greater infiltration of neutrophils into the infarct area. The expression of the MMPs, especially in the db/+ mice, is preceded by an elevated expression of their endogenous tissue inhibitors of metalloproteases (TIMPs) 1, 2, and 3, whereas in the db/db mice, a lower expression of the TIMPs is associated with greater MMP 3 and 9 expression. These results suggest that an imbalance in the MMPs/TIMPs cascade in the diabetic mouse, particularly MMP-9, results in a greater neutrophil invasion, a compromised BBB and consequently a greater insult.
引用
收藏
页码:1029 / 1040
页数:12
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