(Stroke. 2005;36:3.)
© 2005 American Heart Association, Inc.
Letters to the Editor |
Cellular-Fibronectin and Matrix Metalloproteinase-9 in Patients With Stroke
Department of Pathophysiology of Pregnancy
Department of Gynecology
Department of Dermatology, Medical University of Bialystok, Bialystok, Poland
To the Editor:
The article by Castellanos et al on the plasma cellular-fibronectin (c-Fn) and matrix metalloproteinase-9 (MMP-9) concentrations in patients with acute ischemic stroke needs some clarification.1
In the Materials and Methods section it is stated that plasma MMP-9 levels were measured by a commercially available ELISA assay. The Amersham Biosciences, from which the assay was purchased, provides different types of assay for determination of MMP-9. One of them is for human MMP-9 and measures both free pro-MMP-9 and pro-MMP-9 complexed to TIMP-1. The other method, called MMP-9 activity assay, is used for determination of the active form of the compound.
It is not clear which form of MMP-9 was determined in the study. The MMP-9 human assay’s range of detection in plasma is 4 to 128 ng/mL, whereas the median values obtained in the study were within the range of 54 to 225 ng/mL. We therefore guess that the authors did not measure the active form of the enzyme because the assay range is much lower, 0.5 to 16 ng/mL. This could have given different results as to the changes in proteolytic activity, in agreement with findings in a study by our group.2
In our study the total (pro-, active and complexed) concentrations of MMP-9 were significantly higher in peritoneal fluid of women with endometriosis (reproductive-age inflammation-associated disease of women) than of healthy controls. No differences between the 2 groups were found in the concentrations of the active form of the compound. We suggested it was due to the presence of a pro-MMP-9 form and possibly attenuation of the pro-MMP-9 activation processes in peritoneal fluid.2
Castellanos et al1 found that c-Fn was a more specific marker of high risk for cellular hemorrhage and thrombosis. We are in agreement with the authors that increased c-Fn synthesis could be an attempt to decrease endothelial destruction by MMPs. However, we doubt that this explains the positive correlation found between c-Fn and MMP-9. We believe this conclusion would be better founded if activity of the enzyme was measured with the appropriate method.
References
- Castellanos M, Rogelio L, Serena J, Blanco M, Pedraza S, Castillo J, Dàvalos A. Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke. 2004; 35: 1671–1676.
[Abstract/Free Full Text] - Szamatowicz J, Laudanski P, Tomaszewska I. Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1: a possible role in the pathogenesis of endometriosis. Hum Reprod. 2002; 17: 284–288.
[Abstract/Free Full Text]
Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain
Hospital Clínico Universitario Santiago de Compostela, Santiago de Compostela, Spain
Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain
Response:
We thank Drs Laudanski, Szamatowicz, and Laudanska for their comments on our article.1
In our study we determined both free pro-metalloproteinase-9 (MMP-9) and pro-MMP-9 complexed to TIMP-1 using the appropriate Amersham Biosciences ELISA assay kit and so Laudanski and colleagues are right that we have not independently analyzed the MMP-9 active form.1
In Laudanski’s study into the pathogenesis of endometriosis they analyzed both the complexed and the active form of MMP-9 separately, obtaining different levels of the molecule, which allowed them to conclude that there was a disturbed equilibrium between MMP-9 and TIMP-1 in the peritoneal fluid of women with endometriosis.2 In our study we aimed to investigate whether high plasma levels of cellular-fibronectin (c-Fn) and MMP-9 were related to hemorrhagic transformation (HT) in patients with ischemic stroke who had received thrombolytic treatment. As we analyzed the active form together with the complexed MMP-9 levels, we are not able to determine whether a possible imbalance between MMP-9 and its inhibitor might be related to HT in our patients. However, it has recently been demonstrated that only the active MMP-9 form participates in the degradation of the components of the extracellular matrix in an experimental model of cerebral ischemia,3 and so we can hypothesize that the difference in the levels of MMP-9 between patients with and without HT are due to higher levels of the active form. As Laudanski et al suggest, further analysis of both molecules would give us a better understanding of the mechanisms participating in the development of bleeding after cerebral ischemia, and until such a study is performed we can only speculate as to how the c-Fn/MMP-9 positive correlation is to be explained.
Independently of what the precise mechanism may be, our findings demonstrate that high levels of both molecules predict subsequent bleeding in our stroke patients and so has the potential to be of great practical value.
References
- Castellanos M, Leira R, Serena J, Blanco M, Pedraza S, Castillo J, Dávalos A. Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke. 2004; 35: 1671–1676.
[Abstract/Free Full Text] - Szamatowicz J, Laudanski P, Tomaszewska I. Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1: a possible role in the pathogenesis of endometriosis. Hum Reprod. 2002; 17: 284–288.
[Abstract/Free Full Text] - Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL Jr., del Zoppo GJ. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke. 2004; 35: 998–1004.
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