Different DOACs Control Inflammation in Cardiac Ischemia-Reperfusion Differently

Abstract

Rationale: While thrombin is the key protease in thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially distinct receptors. Objective: To study the differential effects of fXa or fIIa inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury (IRI). Methods and Results: Mice were treated with a direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses that induced comparable anticoagulant effects ex vivo and in vivo (tail bleeding assay and FeCl3-induced thrombosis). Myocardial IRI was induced via LAD ligation. We determined infarct size and in vivo aPC generation, analyzed gene expression by RNAseq, and performed immunoblotting and ELISA. The signaling-only 3K3A-aPC variant and inhibitory antibodies that blocked all or only the anticoagulant function of aPC were used to determine the role of aPC. Doses of fIIai and fXai that induced comparable anticoagulant effects resulted in a comparable reduction in infarct size. However, unbiased gene expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai but not fIIai inhibited sterile inflammation by reducing the expression of proinflammatory cytokines (IL-1beta, IL-6, and TNFalpha) as well as NF-κB and inflammasome activation. This anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post myocardial IRI. Mechanistically, in vivo aPC generation was higher with fXai than with fIIai. Inhibition of the anticoagulant and signaling properties of aPC abolished the anti-inflammatory effect associated with fXai, while inhibiting only the anticoagulant function of aPC had no effect. Combining 3K3A-aPC with fIIai reduced the inflammatory response, mimicking the fXai-associated effect. Conclusions: We showed that specific inhibition of coagulation via DOACs had differential effects on gene expression and inflammation, despite comparable anticoagulant effects and infarct sizes. Targeting individual coagulation proteases induces specific cellular responses unrelated to their anticoagulant effect.

Identification of potential biomarkers and immune cell infiltration in acute myocardial infarction (AMI) using bioinformatics strategy

“…Six DEGs (ARG1, CLEC4E, SAMSN1, FKBP5, NAMPTL, and S100A12) were obtained, all of which indicated great performance in identifying patients with STEMI from SCAD with AUC > 0.9 (Figure 3a). However, we noticed differences in our research compared with the previous study, which observed five differentially expressed genes FKBP5, S100P, SAMSN1, CLEC4E, and S100A12 [17][18][19][20][21][22][23][24][25][26]; we observed two additional novel DEGs ARG1 and NAMPTL; different expression of S100P among STEMI and SCAD was failed to be observed in our study. This variety was caused by various preprocessing of the expression data: in our analysis, before DEGs analysis, we performed clustering with gene expression to identify experimentally caused outliers and discarded five samples including three patients with STEMI and 2 with SCAD (Figure 1a).…”

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

“…Indeed, in addition to its effect on p21, aPC reverses glucoseinduced expression of p66 Shc , a mitochondrial protein promoting ROS-generation, in podocytes (glomerular cells) and macrophages (9,11). Furthermore, inhibitors of coagulation factors fIIa (dabigatran) or fXa (rivaroxaban) differentially regulate aPC generation, which is linked to differential gene expression and epigenetic marks (55). Epigenetic control of gene-expression by aPC provides a rational for the long-lasting effects of therapeutic aPC applications despite its short half-life (56) andconsidering the broad cytoprotective effects of aPC -may be relevant in other disease settings (34,57).…”

Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C

“…In our recent follow-up studies, we have investigated the transcriptomic profile of aPC treatment in murine myocardial IRI in comparison to direct oral anticoagulants FXa inhibitor (FXai, rivaroxaban) and FIIa inhibitor (FIIai, dabigatran). In this regard, the dosing regimens for both anticoagulants were experimentally determined to provide comparable anticoagulant effects and the infarct sizes ( 84 ). The results from our study show that the gene expression profile of aPC-treated mice resembled that of mice treated with FXa inhibitor (FXai, rivaroxaban) ( 84 ).…”

“…In this regard, the dosing regimens for both anticoagulants were experimentally determined to provide comparable anticoagulant effects and the infarct sizes ( 84 ). The results from our study show that the gene expression profile of aPC-treated mice resembled that of mice treated with FXa inhibitor (FXai, rivaroxaban) ( 84 ). On the contrary, mice treated with FIIa inhibitor (FIIai, dabigatran) had a markedly different gene expression profile compared to FXai or aPC treated mice.…”