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. 2019 Jan 1;199(1):83–98. doi: 10.1164/rccm.201712-2553OC

Figure 6.

Figure 6.

Enzastaurin reverses hemodynamic parameters, severe vascular remodeling, pulmonary emphysema, cardiac fibrosis, and right ventricular hypertrophy in Sugen5416/hypoxia rats. Experimental pulmonary hypertension was induced in male Sprague-Dawley rats by subcutaneous injection of 20 mg/kg body weight SU5416. Animals were housed for 3 weeks in hypoxic (Hx, 10% O2) conditions, followed by a 5-week period in normoxia (Nx, 21% O2), following daily administration of 5 mg/kg body weight enzastaurin or vehicle control by oral gavage. (A) Right ventricular systolic pressure was measured by pulmonary artery catheterization (n = 4; mean ± SEM; **P < 0.01 vs. Nx control, one-way ANOVA, Sidak post hoc test). (B) Right ventricle hypertrophy is demonstrated by the weight ratio of the right ventricle to the left ventricle and septum (n = 4; mean ± SEM; **P < 0.01 vs. Nx control, #P < 0.05 vs. vehicle control, two-way ANOVA, Tukey post hoc test). (C) Ratio of alveolar wall and alveolar duct pulmonary vessels, (D) their full or partial occlusion (percentage), and (E) their full or partial muscularization (percentage) were assessed in Movat-stained lung sections (n = 4; mean ± SEM; ****P < 0.0001 vs. Nx control, ###P < 0.001, ####P < 0.0001 vs. vehicle control, two-way ANOVA, Tukey post hoc test). (F) Representative Movat lung histology, highlighting large pulmonary vessels. Scale bars, 50 μm. (G) Relative mRNA expression of fragile histidine triad or bone morphogenetic protein receptor type 2 normalized to GAPDH in whole-lung tissue (quantitative PCR; n = 4; mean ± SEM; two-way ANOVA). (H) Representative Movat lung histology, presenting vessel occlusion (scale bars, 200 μm). (I) Percentage of fibrotic tissue compared with total tissue in the right ventricle (n = 4; mean ± SEM; ****P < 0.0001 vs. Nx control, ####P < 0.0001 vs. vehicle control, two-way ANOVA, Tukey post hoc test). (J and K) Representative trichrome stains of whole right ventricle histology (J) and magnified sections (K) are displayed (scale bars, 200 μm). AD = alveolar duct; AW = alveolar wall; BMPR2 = bone morphogenetic protein receptor type 2; Enz = enzastaurin; FHIT = fragile histidine triad; RV = right ventricle; RV/LV+S = weight ratio of the right ventricle to left ventricle and septum weight; RVSP = right ventricular systolic pressure.