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

Figure 1.. Experimental protocol. CAL, coronary artery ligation; %FS, percent fractional shortening; UCG, ultrasound cardiography.

Figure 2.. Effect of rivaroxaban on left ventricular (LV) remodeling after myocardial infarction (MI). Changes in (A) LV end-diastolic diameter (LVDd), (B) LV systolic dimension (LVDs), (C) M-mode percent fractional shortening (%FS), (D) interventricular septum thickness in diastole (IVSTd), and (E) posterior LV wall thickness in diastole (PLWTd)assessed by echocardiography before and at days 1, 7 and 14 after MI in the rivaroxaban and vehicle groups (n=35/group). Data are mean±standard error. *P<0.05 vs. vehicle.

Figure 3.. Effect of rivaroxaban on infarct size at day 7 after myocardial infarction (MI). (A) Representative images of Masson’s-Trichrome stained heart sections of vehicle- and rivaroxaban-treated mice at day 7 after MI. Scale bars=500 μm. (B) Infarct size in vehicle and rivaroxaban-treated mice at day 7 after MI (n=7/group). Data are mean and 95% confidence interval. (C) Body weight and heart weight/tibial length ratio of the vehicle and rivaroxaban-treated mice at day 7 after MI (n=7/group). Data are mean±standard error.

Figure 4.. Characterization of inflammatory response at day 7 after myocardial infarction (MI). (A) Representative images of immunohistochemical staining with Gr-1 and Iba-1 of LV cross-sections in the vehicle- and rivaroxaban-treated mice at day 7 after MI. Scale bars=50 μm (B) Density of Gr-1-positive macrophages and Iba-1-positive granulocytes in the infarcted area of the LV in vehicle- and rivaroxaban-treated mice at day 7 after MI. Data is mean±standard error (n=7/group). LV, left ventricle.

Figure 5.. Effect of rivaroxaban on mRNA expression at day 7 after myocardial infarction (MI). Quantitative results of real-time reverse transcriptase PCR for (A) MMP-2, (B) MMP-9, (C) TIMP-1, (D) Col1a1, (E) Col3a1, (F) TGFb-1, (G) IL-1b, (H) IL-6, (I) TNF-α, (J) MCP-1, (K) ANP and (L) BNP mRNA levels at day 7 after MI. The mRNA level was expressed relative to the level of endogenous control 18S ribosomal RNA (n=15/group). In these box-and-whisker plots, lines within the boxes represent median values; the upper and lower lines of the boxes represent the 75th and 25th percentiles, respectively, and the upper and lower bars outside the boxes represent maximum and minimum values within 1.5-fold the interquartile range from the 75th and 25th percentile, respectively. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; Col, collagen; IL, interleukin; IA, infarcted area; NIA, non-infarcted area; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; PCR, polymerase chain reaction; TGF, tumor growth factor; TIMP, tissue inhibitor of metalloproteinase; TNF , tumor necrosis factor.

Figure 6.. Effect of rivaroxaban on PAR-1 and PAR-2 mRNA expression in the infarcted area at day 7 after myocardial infarction (MI). Quantitative results of real-time reverse transcriptase PCR for (A) PAR-1, (B) PAR-2, (C) PAR-3, and (D) PAR-4 mRNA levels at day7 after MI. The mRNA level was expressed relative to the level of endogenous control 18S ribosomal RNA (n=15/group). See Figure 4 for explanation of the box-and-whisker plots. PAR, protease-activated receptor.

Figure 7.. Effect of rivaroxaban on cardiomyocyte hypertrophy and phosphorylation of extracellular signal-regulated kinase (ERK) in the non-infarcted area. (A) Representative images of the cardiomyocyte cross-sectional area. Scale bars=50 μm. (B) Quantitative analysis of cardiomyocyte cross-sectional area in vehicle and rivaroxaban mice at day 7 after MI (n=7/group). Data are mean±standard error. (C) Representative images of western blot analysis of the phosphorylation of ERK at day 7 after MI. (D) Quantitative analysis of the immunoblots of phosphorylation of ERK at day 7 after MI (n=6/group).