Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies.
OBJECTIVE
The goal of this study was to determine the temporal profile of several matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and laminin (an MMP substrate) in human stroke under different treatment paradigms, including thrombolysis and hypothermia.


METHODS
We serially measured the serum levels of MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, and laminin in 50 patients with acute ischemic stroke using zymography or enzyme-linked immunosorbent assay. Patients were treated with heparin, therapeutic thrombolysis, or hypothermia. Scandinavian Stroke Scale scores were obtained at baseline. Infarct volume was measured with CT scanning on day 4 after stroke onset. Healthy persons were used as control subjects.


RESULTS
MMP-2 and MMP-9 increased during the course of ischemia, whereas intact laminin and TIMP-2 decreased significantly (P<0.05). MMP-9 and laminin levels varied significantly by infarct size (P=0.001) and therapy (P=0.0005). MMP-9 levels were significantly higher in patients treated with tissue plasminogen activator (tPA) compared with patients treated with hypothermia. The cleaved form of MMP-9 was found solely in 4 patients treated with tPA. Intact laminin levels were significantly lower in the tPA group than in the hypothermia group.


CONCLUSIONS
Selected MMPs and TIMPs are involved in the pathophysiology of acute stroke. This is also reflected by changes in laminin. Treatment paradigms differentially influence levels of MMP-9 and laminin. Combination therapies explicitly involving MMP inhibition could be of value in future treatment strategies.
Horstmann
Solveig
S
Department of Neurology, Medical School, University of Heidelberg, Germany.
Kalb
Pamela
P
Koziol
James
J
Gardner
Humphrey
H
Wagner
Simone
S
D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000097:blood / Q000000981:diagnostic imaging / Q000628:therapy; D002544:Cerebral Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000628:therapy; D017364:Collagenases / Q000097:blood; D018450:Disease Progression; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D007036:Hypothermia, Induced; D007797:Laminin / Q000097:blood*; D008297:Male; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D012016:Reference Values; D020521:Stroke / Q000097:blood* / Q000000981:diagnostic imaging / Q000628:therapy; D015912:Thrombolytic Therapy; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood*; D014057:Tomography, X-Ray Computed
D007797:Laminin; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D006493:Heparin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9