Abstract 18832: Local Expression of Coagulation Factor X (FXa) is Increased in Response to Pressure Overload and Mediates Cardiac Hypertrophy and Fibrosis
Introduction: Factor Xa (FXa) is a key components of the coagulation cascade leading to thrombin generation and clot formation. FXa inhibition has been proven to be viable targets for effective anticoagulation treatment. However, accumulating evidence suggest that FXa is also a crucial modulator of cell growth and function through activation of protease-activated receptors (PARs). This study was designed to characterize the relative role of FXa as a direct mediator of cardiac hypertrophy and fibrosis in response to pressure overload (PO) stress.
Methods and Results: Mice subjected to transverse aortic constriction (TAC) for 3 weeks show increased FXa expression and activity in the left ventricle (LV) and in plasma along with an increase in blood coagulation. Treatment of mice with low dose of FXa inhibitor, rivaroxaban (1 mg/kg/d, i.p. for 3 weeks), slightly reduced plasma levels of FXa activity and thrombin anti-thrombin compared to untreated TAC, without any effect on bleeding. Interestingly, rivaroxaban significantly reduced cardiac hypertrophy and fibrosis and improved cardiac function post-TAC. Rivaroxaban treatment also attenuated TAC-induced inflammation as evidenced by a decrease in infiltration of CD45+ and CD3+ T cells and reduced the expression of inflammatory cytokines (IL-1β, IL-6) in the LV, with minimal changes in circulating platelet count. Treatment of isolated neonatal cardiac myocyte with FXa (100 nM) initiated a signaling cascade that culminated to elongated cardiomyocyte hypertrophy. These effects were inhibited by treatment with rivaroxaban and were partially attenuated by treatment with PAR1 or PAR2 antagonists, SCH79797 (5 μM) or ENMD-1068 (5 μM), respectively. Interestingly, FXa treatment also led to cardiac fibroblast proliferation, migration and differentiation to myofibroblasts and increased the expression of inflammatory markers in a PAR1-dependent pathway.
Conclusions: These results indicate that FXa has a direct pro-hypertrophic, pro-fibrotic and pro-inflammatory effects on cardiomyocytes and fibroblasts in vitro and suggest a potential novel molecular mechanism for the observed efficacy of low doses of rivaroxaban treatment on pathological cardiac hypertrophy and dysfunction after PO stress.
Author Disclosures: X. Guo: None. M. Kolpakov: None. B. Hooshdaran: None. L. Vlasenko: None. W. Schappell: None. T. Wang: None. S. Liu: None. D. Crandall: None. P. Andrade-Gordon: None. S.R. Houser: None. A. Sabri: None.
- © 2016 by American Heart Association, Inc.