Background: Coagulation factor XI (FXI) has emerged as a promising antithrombotic target uncoupling thrombosis and hemostasis. Targeting FXI can attenuate angiotensin II (AngII) -induced vascular dysfunction, hypertension and renal damage, thus may be beneficial to prevent atherothrombotic events in high-risk patients. However, the potential role of FXI inhibition on cardiac ischemia reperfusion injury (IRI) in CVD caused by excess neurohormonal activation is still unknown.
Methods: C57BL/6J male mice were treated with Ang II infusion, unilateral nephrectomy and high-salt diet (AngII++) for 4 weeks to model excess neurohormonal activation. FXI antisense oligonucleotide (FXI ASO) or scrambled ASO was injected for 2 weeks. Left anterior descending (LAD) was temporarily ligated for 45 minutes, followed by the reperfusion. After 72 hours, cardiac function and vascular function were analyzed by high frequency ultrasound, real-time PCR, vascular relaxation studies from isolated aortic segment.
Results: FXI ASO administration improved vascular dysfunction and reduced hypertension in the AngII++ operated group compared to control. In cardiac IRI, the inhibition of FXI resulted in better LV ejection fraction and less LV mass and significantly improved endothelial dysfunction compared to mice injected with scrambled ASO and did this to a greater extent in AngII++ than in sham mice. Furthermore, the expression levels of adhesion molecules and the expression of pro-inflammatory targets, such as Vcam-1, CCL2, IL-6, and IL-1β, were significantly decreased in the ischemic myocardium of FXI-depleted mice in the AngII++ following cardiac IRI group compared to scramble ASO with IRI group. Endogenous thrombin potential (ETP) detected by calibrated thrombin generation assay in platelet rich plasma was significantly reduced in FXI ASO compared to scrambled ASO treated AngII++ with IRI mice, whereas the platelet count was not altered, suggesting a role of platelet dependent FXI-thrombin-amplification in cardiac ischemia.
Conclusion: Our results suggest that the inhibition of FXI synthesis by ASO treatment offers cardiovascular protection in cardiac IRI in mice with excess neurohormonal activation via anti-inflammatory effects.
