Author + information
- Received March 18, 2019
- Revision received October 4, 2019
- Accepted October 7, 2019
- Published online January 27, 2020.
- Xinji Guo, PhDa,
- Mikhail A. Kolpakov, MD, PhDa,
- Bahman Hooshdaran, PhDa,
- William Schappell, BSa,
- Tao Wang, MD, PhDa,
- Satoru Eguchi, MD, PhDa,
- Katherine J. Elliott, PhDa,
- Douglas G. Tilley, PhDb,
- A. Koneti Rao, MDc,
- Patricia Andrade-Gordon, PhDd,
- Matthew Bunce, PhDd,
- Chintala Madhu, PhDd,
- Steven R. Houser, PhDa and
- Abdelkarim Sabri, PhDa,∗ ()
- aCardiovascular Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- bCenter of Translational Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- cSol Sherry Thrombosis Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- dJanssen Pharmaceutical, Spring House, Pennsylvania
- ↵∗Address for correspondence:
Dr. Abdelkarim Sabri, Cardiovascular Research Center, Temple University, MERB 1045, 3500 North Broad Street, Philadelphia, Pennsylvania 19140.
• Factor X expression was increased in the heart following pressure overload and in isolated cardiac myocytes and fibroblasts.
• Rivaroxaban treatment at doses that do not affect thrombin generation, blood coagulation or cardiac hemostasis attenuated cardiac inflammation, hypertrophy, and fibrosis caused by pressure overload and improved cardiac diastolic function.
• Activated coagulation factor X induced PAR-1/-2–mediated elongated cardiomyocyte hypertrophy and PAR1-mediated cardiac fibroblast proliferation, migration and differentiation.
• Activated coagulation factor X derived from a cardiac source may represent an important physiologic and pathophysiologic activator of PAR-1/PAR-2.
• Non-anticoagulation dosage of rivaroxaban could provide an effective therapy to attenuate early phases of heart failure development.
Activated factor X is a key component of the coagulation cascade, but whether it directly regulates pathological cardiac remodeling is unclear. In mice subjected to pressure overload stress, cardiac factor X mRNA expression and activity increased concurrently with cardiac hypertrophy, fibrosis, inflammation and diastolic dysfunction, and responses blocked with a low coagulation-independent dose of rivaroxaban. In vitro, neurohormone stressors increased activated factor X expression in both cardiac myocytes and fibroblasts, resulting in activated factor X-mediated activation of protease-activated receptors and pro-hypertrophic and -fibrotic responses, respectively. Thus, inhibition of cardiac-expressed activated factor X could provide an effective therapy for the prevention of adverse cardiac remodeling in hypertensive patients.
- activated coagulation factor X
- cardiac hypertrophy
- protease-activated receptors
This work was supported by the National Institute of Health (HL360338 and HL 360343) and funding from Janssen Pharmaceutical. Dr. Andrade-Gordon has received personal fees from Janssen. Dr. Bunce is an employee of Janssen Research and Development. Dr. Madhu is employed by Janssen; and owns Johnson and Johnson stock. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received March 18, 2019.
- Revision received October 4, 2019.
- Accepted October 7, 2019.
- 2020 The Authors