Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Inhibition of coagulation factor XI improves vascular dysfunction and decreases cardiac inflammation in cardiac ischemia/reperfusion injury
Q. Luo1, M. Molitor2, S. Finger3, P. Wenzel2
1Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;
Background: There is emerging evidence that coagulation factor XI (FXI) might be a suitable target for antithrombotic therapy because it reduces thrombosis without increasing bleeding risk. Patients with decreased levels of FXI are at reduced risk of thromboembolic events and cardiovascular diseases. We have recently shown that depletion of FXI inhibits the vascular coagulation-inflammatory circuit in angiotensin II-induced arterial hypertension mouse model. However, the effect of FXI depletion on cardiac inflammation and vascular function in ischemia/reperfusion injury is unknown.
 
Material and Methods: 8-12 weeks old C57BL/6J male mice were injected intraperitoneally with FXI antisense oligonucleotide (FXI ASO) or scrambled controls. We temporarily ligated the left anterior descending (LAD) for 45 minutes to induce myocardial ischemia, followed by the reperfusion (ischemia/reperfusion injury, I/R injury). 3 days after the operation, myocardial inflammation and vascular function were analyzed by flow cytometry, real-time PCR, vascular relaxation studies from isolated aortic segment in organ chamber and chemiluminescence photon counting of oxidative burst in whole blood.
 
Results: Hepatic mRNA expression of FXI was effectively reduced after treatment with FXI ASO. Compared to scrambled ASO injected mice, oxidative burst from whole blood and endothelial dysfunction were significantly reduced in FXI ASO injected mice at 3d post I/R injury. Compared to controls, depletion of FXI attenuated cardiac infiltration of CD45+CD11b+ myelomonocytic cells, especially LyG-LyChigh monocytes and LyG+ neutrophils at day 3 after I/R injury. Furthermore, the expression levels of pro-inflammatory cytokines Vcam-1, CCL2, IL-6 and IL-1beta in ischemic myocardium were significantly decreased after inhibition of FXI in mice 3d post I/R injury.
 
Conclusion: Our results suggest that depletion of FXI leads to reduction of vascular dysfunction and cardiac inflammatory response after I/R injury, indicating that FXI could be a potential target for further treatment in cardiac I/R injury.
 

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