A Matrix Metalloproteinase Protein Array Reveals a Strong Relation Between MMP-9 and MMP-13 With Diffusion-Weighted Image Lesion Increase in Human Stroke

Abstract

Background and Purpose-Matrix metalloproteinases (MMPs) are involved in tissue destruction produced by the neuroinflammatory response that follows ischemic stroke. In the present study we use an MMP array to investigate the blood levels of several MMPs in stroke patients and its relation with brain tissue damage and neurological outcome. Methods-Twenty-four patients with middle cerebral artery occlusion who received thrombolytic therapy were included.Blood samples were drawn before tissue plasminogen activator treatment and an MMP array (multiplex enzyme-linked immunosorbent assay [ELISA]) was performed including gelatinases (MMP-2 and MMP-9), collagenases (MMP-1, MMP-8, and MMP-13), stromelysines (MMP-3 and MMP-10), and MMP endogen inhibitors (TIMP-1 and TIMP-2). To assess tissue lesion a serial multimodal MRI study was performed (pretreatment and at 24 hours). Results-Neither initial diffusion lesion nor hypoperfused volume was associated with metalloproteinase expression within the first 3 hours after stroke onset. Nevertheless, a strong correlation was found between MMP-9 and MMP-13 with diffusion-weighted image (DWI) lesion expansion (rϭ0.54, Pϭ0.05 and rϭ0.60, Pϭ0.017, respectively). Baseline levels of both MMP-9 (OR, 14;95% CI, 1.5 to 131; Pϭ0.019) and MMP-13 (OR, 73; 95% CI, 3.9 to 1388; Pϭ0.004) were independent predictors of final increase in brain infarct volume at 24 hours. Conclusions-Our results demonstrate that within the neuroinflammatory response, high levels of MMP-9 and MMP-13 are involved in DWI lesion growth despite thrombolytic therapy, suggesting its ultra-early role in brain injury.

Blood Biomarkers of Ischemic Stroke

“…A larger infarct volume might also lead to a greater inflammatory response to the ischemic tissue. This is supported by studies showing elevated inflammatory markers are associated with infarct volume, including TNF-α [53], IL-6 [54,55], ICAM-1 [53], MMP-2 and MMP-9 [53,56].…”

“…IL-6 levels >21.5 pg/ml in plasma and 6.3 pg/ml in CSF predict END [54]. MMP-9 and MMP-13 independently predict lesion volume expansion in ischemic stroke [56]. CSF nitric oxide levels >5umol/ml also predict END [70].…”

In Vivo Near-Infrared Fluorescence Imaging of Matrix Metalloproteinase Activity after Cerebral Ischemia

“…However, the study by Rosell et al (2005) has shown no correlation between the plasma levels of MMP-1, -2, -3, -8, and -10 and the extent of the lesion. In a subset of MCAO mice injected with the MMP-activatable probe, multiparametric MRI was performed immediately and 24 h after reperfusion to assess the development of the ischemic lesion.…”

“…Matrix metalloproteinase-9 is detected in human brain tissue sections after ischemic and hemorrhagic strokes (Rosell et al, 2006). Plasma levels of MMP-9 are increased in patients with acute stroke and correlate with the clinical outcome (Montaner et al, 2003a;Rosell et al, 2005). Patients with higher plasma MMP-9 levels are also more likely to undergo hemorrhagic transformation after tissue plasminogen activator treatment (Montaner et al, 2003b).…”

The expression of matrix metalloproteinase-13 is increased in vessels with blood–brain barrier impairment in a stroke-prone hypertensive model

“…In addition, it was reported using an MMP protein array that high levels of MMP-9 and MMP-13, also known as collagenase-3, are involved in diffusion-weighted image lesion growth. 29 It remains to be clarified whether MMP-13 is involved in the BBB disruption.…”