Background: An enhanced renin‐angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease‐activated receptors ( PAR ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren‐TG). Methods and Results: The 12‐ to 16‐week‐old Ren‐TG and wild‐type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren‐TG compared with the wild‐type mice and was reduced by 12 mg/kg of rivaroxaban ( P <0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8‐month‐old Ren‐TG than in the wild‐type mice (69.6±29 versus 20.1±8.2 μg/day; P <0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 μg/day ( P <0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren‐TG. The renal expression of PAR ‐2 was increased in the Ren‐TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR ‐2 and inflammatory genes and nuclear factor–‐κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR ‐2 knockdown by small interfering RNA also attenuated the PAR ‐2‐related inflammatory gene expressions. Conclusions: These findings indicate that rivaroxaban exerts protective effects against angiotensin II–induced renal damage, partly through inhibition of the PAR ‐2 signaling‐mediated inflammatory response.

Background: Although PAR‐1 (protease‐activated receptor‐1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR ‐1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR ‐1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin–angiotensin system activation using renin‐overexpressing hypertensive (Ren‐Tg) mice. Methods and Results: We treated 12‐ to 16‐week‐old male wild‐type ( WT ) mice and Ren‐Tg mice with continuous subcutaneous infusion of the PAR ‐1 antagonist SCH 79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren‐Tg mice than in WT mice, and SCH 79797 treatment significantly decreased these thicknesses in Ren‐Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren‐Tg mice than in WT mice, and both conditions were attenuated by SCH 79797 treatment. Cardiac mRNA expression levels of PAR ‐1, TNF‐α (tumor necrosis factor‐α), TGF‐β1 (transforming growth factor‐β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β‐myosin heavy chain (β‐ MHC ) to α‐ MHC were all greater in Ren‐Tg mice than in WT mice; SCH 79797 treatment attenuated these increases in Ren‐Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren‐Tg mice than in WT mice, and both conditions were unaffected by SCH 79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal‐regulated kinase 1/2) phosphorylation, and SCH 79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR ‐1, TGF ‐β1, and COL 3A1 were enhanced by factor Xa, and all were inhibited by SCH 79797. Conclusions: The results indicate that PAR ‐1 signaling is involved in cardiac remodeling induced by renin–angiotensin system activation, which may provide a novel therapeutic target for heart failure.

Background:Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) level is a reliable prognostic biomarker in acute coronary syndrome. However, it is unclear whether its plasma level at acute phase is related to the long-term prognosis in patients with ST-segment elevation acute myocardial infarction (STEMI).Methods and Results:We prospectively examined the relation between plasma sLOX-1 level on admission and prognosis in 153 consecutive STEMI patients admitted within 24 h of onset. Primary percutaneous coronary intervention was performed in 144 patients. The patients were divided into 2 groups by the median value (71 pg/ml) of plasma sLOX-1 level on admission [sLOX-1 level ≤71 pg/ml (n=77) and >71 pg/ml (n=76)], and were followed for median of 1,156 days. All-cause mortality and the combined endpoints of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and recurrent MI were both significantly higher in patients with sLOX-1 values above median than in those below median (25.0% vs. 3.9%, P<0.001, and 19.4% vs. 6.5%, P=0.019 by log-rank test, respectively). Even after adjustment for confounders, a level of sLOX-1 above median was an independent predictor for all-cause mortality (hazard ratio (HR): 5.893; 95% confidence interval (CI): 1.665–20.854, P=0.006) and MACE (HR: 3.457; 95% CI: 1.164–10.270, P=0.030).Conclusions:Elevated plasma sLOX-1 level on admission independently predicts long-term all-cause mortality and MACE after STEMI. (Circ J 2015; 79: 641–648)