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Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway.

ABSTRACT: The purpose of this study was use molecular imaging targeting coagulation pathway and inflammation to better understand the pathophysiology of silent brain ischemia (SBI) and monitor the effects of factor XIIa inhibition.SBI can be observed in patients who undergo invasive vascular procedures. Unlike acute stroke, the diffuse nature of SBI and its less tangible clinical symptoms make this disease difficult to diagnose and treat.We induced SBI in mice by intra-arterial injection of fluorescently labeled microbeads or fractionated clot into the carotid artery. After SBI induction, diffusion-weighted magnetic resonance imaging was performed to confirm the presence of microinfarcts in asymptomatic mice. Molecular imaging targeting the downstream factor XIII activity (single-photon emission computed tomography/computed tomography) at 3 h and myeloperoxidase activity (magnetic resonance imaging) on day 3 after SBI induction were performed, without and with the intravenous administration of a recombinant selective factor XIIa inhibitor derived from the hematophagous insect Triatoma infestans (rHA-Infestin-4). Statistical comparisons between 2 groups were evaluated by the Student t test or Mann-Whitney U test.In SBI-induced mice, we found abnormal activation of the coagulation cascade (factor XIII activity) and increased inflammation (myeloperoxidase activity) close to where emboli lodge in the brain. rHA-Infestin-4 administration significantly reduced ischemic damage (53% to 85% reduction of infarct volume, p < 0.05) and pathological coagulation (35% to 39% reduction of factor XIII activity, p < 0.05) without increasing hemorrhagic frequency. Myeloperoxidase activity, when normalized to the infarct volume, did not significantly change with rHA-Infestin-4 treatment, suggesting that this treatment does not further decrease inflammation other than that resulting from the reduction in infarct volume.Focal intracerebral clotting and inflammatory activity are part of the pathophysiology underlying SBI. Inhibiting factor XIIa with rHA-Infestin-4 may present a safe and effective treatment to decrease the morbidity of SBI.

SUBMITTER: Chen JW

PROVIDER: S-EPMC3502014 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway.

Chen John W JW Figueiredo Jose-Luiz JL Wojtkiewicz Gregory R GR Siegel Cory C Iwamoto Yoshiko Y Kim Dong-Eog DE Nolte Marc W MW Dickneite Gerhard G Weissleder Ralph R Nahrendorf Matthias M

JACC. Cardiovascular imaging 20121101 11

<h4>Objectives</h4>The purpose of this study was use molecular imaging targeting coagulation pathway and inflammation to better understand the pathophysiology of silent brain ischemia (SBI) and monitor the effects of factor XIIa inhibition.<h4>Background</h4>SBI can be observed in patients who undergo invasive vascular procedures. Unlike acute stroke, the diffuse nature of SBI and its less tangible clinical symptoms make this disease difficult to diagnose and treat.<h4>Methods</h4>We induced SBI ...[more]

PMID: 23153913

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Project description:Mast cell (MC) activation is associated with myocardial ischemia reperfusion injury (MIRI). Suppression of MC degranulation might be a target of anti-MIRI. This study aimed to determine whether clemastine fumarate (CLE) could attenuate MIRI by inhibiting MC degranulation. A rat ischemia and reperfusion (I/R) model was established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Compound 48/80 (C48/80) was used to promote MC degranulation. The protective effect of CLE by inhibiting MC degranulation on I/R injury was detected by cardiac function, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, arrhythmia, and myocardial enzyme detection. Inflammatory factor mRNA levels, such as TNF-α, interleukin (IL)-1β, and IL-6, were detected. Cultured RBL-2H3 mast cells were pretreated with CLE and subjected to C48/80 treatment to determine whether CLE suppressed MC degranulation. Degranulation of MCs was visualized using tryptase release, Cell Counting Kit-8 (CCK-8), and cell toluidine blue (TB) staining. RBL cells were conditionally cultured with H9C2 cells to explore whether CLE could reverse the apoptosis of cardiomyocytes induced by MC degranulation. Apoptosis of H9C2 cells was detected by CCK-8, the LDH Cytotoxicity Assay Kit (LDH), TUNEL staining, and protein expression of BAX and Bcl-2. We found that CLE pretreatment further inhibited cardiac injury manifested by decreased infarct size, histopathological changes, arrhythmias, MC degranulation, and myocardial enzyme levels, improving cardiac function compared with that in the I/R group. C48/80 combined with I/R exacerbated these changes. However, pretreatment with CLE for C48/80 combined with I/R significantly reversed these injuries. In addition, CLE pretreatment improved the vitality of RBL cells and reduced tryptase release in vitro. Similarly, the supernatant of RBL cells pretreated with CLE decreased the cytotoxicity, TUNEL-positive cell rate, and BAX expression of conditioned H9C2 cells and increased the cell vitality and expression of Bcl-2. These results suggested that pretreatment with CLE confers protection against I/R injury by inhibiting MC degranulation.

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Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway.

Publications

Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway.

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