Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Factor <jats:styled-content style="fixed-case">VII</jats:styled-content> activating protease (<jats:styled-content style="fixed-case">FSAP</jats:styled-content>) is a circulating protease with a putative role in hemostasis, remodeling and inflammation. A polymorphism giving rise to low proteolytic activity has been associated with an increased risk of stroke and carotid stenosis. To date, no <jats:italic>in vivo</jats:italic> studies or mechanistic information is available to explain these results. Based on the polymorphism data we hypothesize that a lack of endogenous <jats:styled-content style="fixed-case">FSAP</jats:styled-content> will increase the severity of stroke. Stroke was induced by applying thrombin in the middle cerebral artery in wild‐type (<jats:styled-content style="fixed-case">WT</jats:styled-content>) and <jats:styled-content style="fixed-case">FSAP</jats:styled-content><jats:sup>−/−</jats:sup> mice. Increased stroke volume and worsened neurological deficit were observed in <jats:styled-content style="fixed-case">FSAP</jats:styled-content><jats:sup>−/−</jats:sup> mice. Raised levels of <jats:styled-content style="fixed-case">FSAP</jats:styled-content> protein were detected in the infarcted area of <jats:styled-content style="fixed-case">WT</jats:styled-content> mice together with enhanced leukocyte infiltration and apoptosis in <jats:styled-content style="fixed-case">FSAP</jats:styled-content><jats:sup>−/−</jats:sup> mice. There was a concomitant increase in the activation of the <jats:styled-content style="fixed-case">NF</jats:styled-content>κB pathway and decrease in expression of the <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/<jats:styled-content style="fixed-case">AKT</jats:styled-content> pathway proteins. At a cellular level, <jats:styled-content style="fixed-case">FSAP</jats:styled-content> increased cell survival and decreased apoptosis in primary cortical neurons and astrocytes exposed to t<jats:styled-content style="fixed-case">PA</jats:styled-content>/<jats:styled-content style="fixed-case">NMDA</jats:styled-content> excitotoxicity or oxygen glucose deprivation (<jats:styled-content style="fixed-case">OGD</jats:styled-content>)/reoxygenation, respectively. This was mediated via the <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/<jats:styled-content style="fixed-case">AKT</jats:styled-content> pathway with involvement of the protease activated receptor‐1. To corroborate the human epidemiological data, which link <jats:styled-content style="fixed-case">FSAP</jats:styled-content> with stroke, we now show that the lack of <jats:styled-content style="fixed-case">FSAP</jats:styled-content> in mice worsens the outcome of stroke. In the absence of <jats:styled-content style="fixed-case">FSAP</jats:styled-content> there was a stronger inflammatory response and lower cell survival due to insufficient activation of the <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/<jats:styled-content style="fixed-case">AKT</jats:styled-content> pathway.</jats:p>