OC 25.4 - Coagulation factor XI contributes to vascular dysfunction and cardiac inflammation in ischemia/reperfusion injury in mice with excess neurohormonal activation

Background: Hypertension is a leading risk factor for cardiovascular disease (CVD). The patients with hypertension and renal failure are more susceptible to ischemia/reperfusion injury (IRI). Targeting coagulation FXI attenuates angiotensin II -induced vascular dysfunction, hypertension and renal damage. Currently, the usefulness of FXI ASOs is evaluated in clinical trials in patients with end-stage renal disease. However, the potential role of FXI on cardiac IRI in CVD caused by excess neurohormonal activation is still unknown.

Aims: Using the FXI-depleted mice to investigate the role of FXI on cardiac IRI in excess neurohormonal activation.

Methods: 9-12 weeks old C57BL/6J male mice were treated with angiotensin II (AngII) infusion, uninephrectomy and high-salt diet (ANS) for 4 weeks to model excess neurohormonal activation. FXI ASO or scrambled controls were injected for 2 weeks. Left anterior descending (LAD) was temporarily ligated for 45 minutes, followed by the reperfusion. After 72 hours, cardiac function, myocardial inflammation and vascular function were analyzed by high frequency ultrasound, flow cytometry, real-time PCR, vascular relaxation studies from isolated aortic segment.

Results: Inhibition of FXI resulted in better LVEF and less LV mass compared to scrambled ASO treated mice, suggesting that inhibition of FXI can improve cardiac function and prevent cardiac hypertrophy in RAAS-induced CVD. Endothelial dysfunction were significantly reduced in ANS IRI mice when inhibiting FXI. Depletion of FXI attenuated cardiac infiltration of CD45+ cells, LyChigh monocytes, and LyG+ neutrophils in IRI compared to controls. Furthermore, the expression levels 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 ANS IRI group.

Conclusion(s): Our results suggest that inhibition of FXI has cardioprotective effect in cardiac IRI in mice with excess neurohormonal activation. Targeting FXI in disease states of hypertension with end-organ damage may attenuate cardiac dysfunction and avert development of HF.