Rivaroxaban Suppresses the Progression of Ischemic Cardiomyopathy in a Murine Model of Diet-Induced Myocardial Infarction

Abstract

Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling.Methods: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61h/h mice (Hypo E mice) that developed MI by high-fat diet loading.Results: Hypo E mice were fed rivaroxaban-containing (n = 49) or control chow diets (n = 126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p = 0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes.In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts.Conclusions: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway.

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models

“…Although some anti-inflammatory effects, improvement of hypercoagulable actions such as disseminated intravascular coagulation (DIC), additional acute lung injury from endotoxemia [ 19 , 36 , 50 ], and additional vasculoprotective properties of RVX have been proposed in different in vitro and tissue models [ 14 , 15 , 20 , 21 , 23 – 25 ] (see Table 2 ), a beneficial effect on LPS induced acute vascular inflammatory response in vivo was not investigated yet. In murine macrophages and human tubular cells stimulated with FXa, RVX treatment was shown to reduce the expression of TNF-α, IL-1β, and MCP-1 [ 14 , 62 ].…”

“…In murine macrophages and human tubular cells stimulated with FXa, RVX treatment was shown to reduce the expression of TNF-α, IL-1β, and MCP-1 [ 14 , 62 ]. Similarly, RVX dampened the expression of VCAM-1, ICAM-1, MCP-1, IL-8, CXCL1, CXCL2, TF in thrombin stimulated human endothelial cells [ 19 ], as well as IL-6, IL-1β, TNF-α, MMP9, and COL-1 expression in hypoxic cardiac myocytes and fibroblasts [ 23 ]. Similarly, also TNF-α, MCP-1, IL-6 expression in angiotensin II-induced inflammatory response in human podocytes was modulated by RVX [ 24 ].…”

“…Interestingly, a recent study has shown a cardioprotective effect of RVX pre-treatment in ischaemic cardiomyopathy in mice model with diet-induced myocardial infarction [ 23 ]. This study has shown that attenuation of cardiac remodeling, fibrosis, alleviation of the aortic root and coronary arteries atherosclerosis is dependent on the reduction of IL-1β, TNF-α, IL-6 cardiac mRNA expression, and nuclear factor kappa B (NF-κB) activation pathway in RVX pre-treated group.…”

“…In addition to this, experimental studies proposed a series of vascular protective properties of NOAC via inhibition of FXa [ 14 – 26 ]. These include potential anti-inflammatory effects [ 15 , 19 – 21 , 23 , 24 , 27 ], that might perhaps impact vascular function and pathology [ 14 , 25 ]. Indeed inflammation is one of the main contributing factors in coronary artery disease leading to the development of atherosclerosis [ 28 ].…”

Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice

“… 18 – 22 Furthermore, in several experimental models of atherosclerosis, atrial fibrosis and ischemic cardiomyopathy, rivaroxaban also suppressed proinflammatory cytokines. 16 – 18 , 34 Based on these findings, it is conceivable that the cardioprotective effects of rivaroxaban are mediated through inhibition of PAR-1 and PAR2 in the infarcted area.…”