Journal: American Journal of Respiratory and Critical Care Medicine

Article Title: Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor

doi: 10.1164/rccm.201710-2079OC

Figure Lengend Snippet: Pharmacological inhibition of HIF-2α (hypoxia-inducible factor-2α) inhibits severe pulmonary arterial hypertension (PAH) in Egln1Tie2Cre mice. (A) Drastic decrease in right ventricular systolic pressure (RVSP) in C76 (compound 76)-treated Egln1Tie2Cre (CKO) mice compared with vehicle-treated mice. Three-week-old Egln1Tie2Cre mice exhibiting PAH were treated with either vehicle (0.5% DMSO) or C76 for 12 weeks. (B and C) Echocardiography measurement of pulmonary artery (PA) function showing normalization of PA acceleration time/ejection time (AT/ET) ratio in C76-treated Egln1Tie2Cre mice. (D) Representative micrographs of Russell-Movat pentachrome staining, showing inhibited obliterative pulmonary vascular remodeling in C76-treated Egln1Tie2Cre mice. Arrows indicate pulmonary vessels with severe remodeling. (E) Reduced occlusive lesions by C76 treatment in Egln1Tie2Cre mice. Notably, there were no occlusive large vessels (>100 μm) in C76-treated Egln1Tie2Cre mice. *P < 0.05, **P < 0.01, and ***P < 0.001. (A and C) One-way ANOVA with Tukey post hoc analysis for multiple group comparisons; and (E) Mann-Whitney test. (D) Scale bars: 50 μm. Br = bronchiole; V = vessel; Veh = vehicle; WT = wild type.

Article Snippet: For histological assessment, sections were stained with a Russell-Movat pentachrome staining kit (American MasterTech) or with a trichrome stain (Masson) kit (Sigma-Aldrich) according to the manufacturer’s instructions ( 17 ).

Techniques: Inhibition, Staining, MANN-WHITNEY

Journal: American Journal of Respiratory and Critical Care Medicine

Article Title: Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor

doi: 10.1164/rccm.201710-2079OC

Figure Lengend Snippet: HIF-2α (hypoxia-inducible factor-2α) inhibition reverses severe pulmonary arterial hypertension in Sugen 5416/hypoxia (SuHx) rats. (A) Diagram showing the experimental timeline including C76 (compound 76) treatment in SuHx rats. (B) C76 treatment reduced right ventricular systolic pressure in SuHx rats. (C) Echocardiography measurements showing improvement in pulmonary artery (PA) diastolic function by C76 treatment in SuHx rats. (D–F) Representative images of Russell-Movat pentachrome staining (D) and vascular lesion quantification (E and F) demonstrating inhibited pulmonary vascular remodeling including reduction in occlusive lesions and PA wall thickness in C76-treated SuHx rats. Arrows point to pulmonary vessels with occlusive vascular remodeling. *P < 0.05, **P < 0.01, and ***P < 0.001. (E) Mann-Whitney test. (B, C, and F) One-way ANOVA with Tukey post hoc analysis for multiple group comparisons. (D) Scale bars: 200 μm. mpk = milligrams per kilogram; PA AT/ET = PA acceleration time/ejection time ratio; RVSP = right ventricular systolic pressure; V = vessel.

Article Snippet: For histological assessment, sections were stained with a Russell-Movat pentachrome staining kit (American MasterTech) or with a trichrome stain (Masson) kit (Sigma-Aldrich) according to the manufacturer’s instructions ( 17 ).

Techniques: Inhibition, Staining, MANN-WHITNEY

Journal: American Journal of Respiratory and Critical Care Medicine

Article Title: Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor

doi: 10.1164/rccm.201710-2079OC

Figure Lengend Snippet: HIF-2α (hypoxia-inducible factor-2α) inhibition halts pulmonary arterial hypertension progression and promotes survival of monocrotaline (MCT) rats. (A) Diagram showing the experimental timeline for C76 (compound 76) treatment in MCT rats. (B–D) C76 treatment reduced right ventricular systolic pressure (B) and right ventricular (RV) hypertrophy (C) and normalized RV contractility (D). (E) Representative micrographs of Russell-Movat pentachrome staining of MCT rat lungs. Arrows indicate vascular lesions. (F) Quantification of pulmonary arterial wall thickness in MCT rat lungs. (G) Marked increase in survival of C76-treated MCT rats compared with vehicle controls. The rats were challenged with MCT at (B–F) 32 mg/kg or (G) 35 mg/kg. **P < 0.01, ***P < 0.001. (B–D and F) One-way ANOVA with Tukey post hoc analysis for multiple group comparisons; and (G) log-rank (Mantel-Cox) test. (E) Scale bar: 50 μm. RV FAC = right ventricular fractional area change; RV/(LV + S) = ratio of right ventricle to left ventricle plus interventricular septum; RVSP = right ventricular systolic pressure; V = vessel.

Article Snippet: For histological assessment, sections were stained with a Russell-Movat pentachrome staining kit (American MasterTech) or with a trichrome stain (Masson) kit (Sigma-Aldrich) according to the manufacturer’s instructions ( 17 ).

Techniques: Inhibition, Staining