Hidekazu Kondo1, Ichitaro Abe2, Akira Fukui2, Shotaro Saito2, Miho Miyoshi2, Kohei Aoki3, Tetsuji Shinohara2, Yasushi Teshima2, Kunio Yufu2, Naohiko Takahashi2. 1. Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan. Electronic address: hkondo@oita-u.ac.jp. 2. Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan. 3. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan.
Abstract
BACKGROUND: Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. METHODS: Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. RESULTS: TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. CONCLUSIONS: These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.
BACKGROUND: Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. METHODS: Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. RESULTS: TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. CONCLUSIONS: These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.
Authors: Songnan Wen; Cristina Pislaru; Kristi H Monahan; Stephanie M Barnes; David O Hodge; Douglas L Packer; Sorin V Pislaru; Samuel J Asirvatham Journal: Cardiovasc Drugs Ther Date: 2021-05-18 Impact factor: 3.947
Authors: Fumin Fu; Michael Pietropaolo; Lei Cui; Shilpa Pandit; Weiyan Li; Oleg Tarnavski; Suraj S Shetty; Jing Liu; Jennifer M Lussier; Yutaka Murakami; Prabhjit K Grewal; Galina Deyneko; Gordon M Turner; Andrew K P Taggart; M Gerard Waters; Shaun Coughlin; Yuichiro Adachi Journal: PLoS One Date: 2022-01-07 Impact factor: 3.240
Authors: Xinji Guo; Mikhail A Kolpakov; Bahman Hooshdaran; William Schappell; Tao Wang; Satoru Eguchi; Katherine J Elliott; Douglas G Tilley; A Koneti Rao; Patricia Andrade-Gordon; Matthew Bunce; Chintala Madhu; Steven R Houser; Abdelkarim Sabri Journal: JACC Basic Transl Sci Date: 2020-01-27