Matrix metalloproteinases at key junctions in the pathomechanism of stroke

Abstract

Matrix metalloproteinases play a crucial role in the remodelling of the extracellular matrix through direct degradation of its structural proteins and control of extracellular signalling. The most common cause of ischemic brain damage is an atherothrombotic lesion in the supplying arteries. The progress of the atherosclerotic plaque development and the related thrombotic complications are mediated in part by matrix metalloproteinases. In addition to their role in the underlying disease, various members of this protease family are upregulated in the acute phase of ischemic brain damage as well as in the post-ischemic brain recovery following stroke. This review summarizes the current understanding of the matrix metalloproteinase-related molecular events at three stages of the ischemic cerebrovascular disease (in the atherosclerotic plaque, in the neurovascular unit of the brain and in the regenerating brain tissue).

Metalloproteinases of the extracellular matrix and their inhibitors

“…The "Met-turn" motif, which is located below the catalytic zinc-binding site, is responsible for forming the correct structure around the zinc ion. The fourth ligand of the catalytic zinc is water and this initiates the activation mechanism of enzymatic hydrolysis (Lipka and Boratyński, 2008;Murphy and Nagase, 2008;Groblewska et al 2010;Tallant et al 2010;Rottenberger and Kolev, 2011).…”

“…Under physiological conditions, the activity of metalloproteinases can be controlled at several levels (Żebrowski et al, 2003;Dziankowska-Bartkowiak et al, 2004;Śliwowska and Kopczyński, 2005;Kowalski et al, 2008;Kwiatkowski et al, 2008;Łukasiewicz et al, 2008;Groblewska et al, 2010;Gorman et al, 2011;Rottenberger and Kolev, 2011): 1) by stimulating the transcription of genes encoding growth factors, cytokines (IL-1, TNF-α), hormones (parathyroid hormone) and bacterial products (lipopolysaccharide); 2) as a result of post-translational modifications (proenzyme activation); 3) through the action of a family of endogenous tissue inhibitors of metalloproteinases (TIMPs) and inhibitors of serine proteases (serpins); 4) by adjusting the level of enzymes through sequestration of intracellular vesicles; 5) through the acidity of the environment; 6) by the level of substrate specificity.…”

“…They are produced by the same cells as MMPs. Their expression is controlled during development and tissue differentiation (Dziankowska-Bartkowiak et al, 2004;Kowalski et al, 2008;Lipka and Boratyński, 2008;Murphy and Nagase, 2008;Rottenberger and Kolev, 2011).…”

“…A total of 28 matrix metalloproteinases have been identified, 23 of which are present in humans (Konopka and Brzezińska-Błaszczyk, 2008;Kowalski et al, 2008;Murphy and Nagase, 2008;Rottenberger and Kolev, 2011). In humans, MMPs are synthesized in several cells, e.g.…”