Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice.
Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban.
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China.
Dan
D
Yang
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China.
Junjie
J
Shao
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China.
Ruifeng
R
Hu
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China.
Haimei
H
Chen
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China. xieping76@hotmail.com.|Department of Pathology, Shanghai KingMed Diagnostics, Shanghai, 201321, P.R. China. xieping76@hotmail.com.
Ping
P
Xie
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, P.R. China. cliu6688@yahoo.com.
Chang
0000-0003-3879-7302
C
Liu
D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors / Q000008:administration & dosage*; D017127:Glycation End Products, Advanced / Q000008:administration & dosage; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000069552:Rivaroxaban / Q000008:administration & dosage*; D015398:Signal Transduction
D016207:Cytokines; D065427:Factor Xa Inhibitors; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000069552:Rivaroxaban