Even in the absence of manifest stroke, AF is a risk factor for cognitive impairment and hippocampal atrophy. Therefore, cognition and measures of structural brain integrity should be considered in the evaluation of novel treatments for AF.

The serpin antithrombin III (AT III), the most important natural inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in experimental models of sepsis, septic shock, and disseminated intravascular coagulation. Moreover, clinical observations suggest a possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is not yet entirely understood. We show here that AT III potently blocks the activation of nuclear factor B (NF-B), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-B in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-B activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IB␣. In parallel to reducing NF-B activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-␣, and tissue factor, genes known to be under the control of NF-B. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-B activation supports the current understanding that the inhibitory potency of AT III depends on the interaction of AT III with heparinlike cell surface glycosaminoglycans. This hypothesis was underscored by the finding that the AT III ␤-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-B transactivation than ␣-AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-B activation. IntroductionAntithrombin is one of the most important endogenous regulators of coagulation, acting as the major inhibitor of thrombin and interfering with several plasma proteases such as kallikrein and factors IXa, Xa, XIa, and XIIa. 1 Apart from its role in hemostasis, there is accumulating evidence that antithrombin III (AT III) exerts anti-inflammatory properties and improves survival in animalsepsis models and disseminated intravascular coagulation (DIC). [2][3][4] There are a number of compelling reasons why AT III may also be an effective therapeutic agent in patients with sepsis. [5][6][7] AT III was shown to reduce leukocyte-endothelial interaction, 8 to prevent microvascular leakage, 9 and to ameliorate ischemia/reperfusion injury. 10 These effects, however, seem to result only in part from interference of AT III with thrombin activity because inhibition of thrombin generation alone did not prove similarly effective. 11,12 The beneficial effects of AT III rather appear mainly to result from direct, thrombin-independent effects on vascular cells. AT III was found to stimulate nitric oxide synthesis in vascular smooth muscle cells, 13 to inhibit migration and adhesion of neutrophils, 14 and to attenuate cytokine production in monocytes and endothelial cells (ECs) 15...

Tissue factor (TF), the primary initiator of blood coagulation with structural homology to the cytokine receptor family, has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Within the vasculature, monocytes and endothelial cells (EC) can be activated to synthesize TF depending on the induction of NF-κB. Despite the undisputed value of cyclosporin A (CsA) as an immunosuppressant, problems have emerged due to induction of vascular changes by a poorly understood mechanism. We demonstrate that CsA has opposite effects on TF gene expression, inhibiting NF-κB-mediated TF gene transcription in monocytes but enhancing it in EC. To test whether CsA binding proteins (cyclophilins) can mediate these CsA effects we used a nonimmunosuppressant analog of CsA that binds to cyclophilins but does not inhibit the Ca2+/calmodulin-dependent phosphatase calcineurin (Cn). This drug lacked regulatory function for NF-κB and TF expression suggesting that Cn is responsible for the inverse gene regulation. The key function of Cn was supported by experiments demonstrating that other phosphatase inhibitors also either positively or negatively regulated NF-κB in monocytes and EC. Calcineurin was demonstrated to regulate NF-κB activation at the level of IκBα degradation, because agonist-induced phosphorylation and subsequent degradation of IκBα is prevented by Cn inhibitors in monocytes but enhanced in EC. These data identify Cn as an opposite regulator in generating transcriptionally active NF-κB, and they confirm the presumption that the ability of Cn to participate in NF-κB transactivation is not T cell specific.