Abstract 16120: Macrophage Specific Deletion of Hypoxia Inducible Factor-1 alpha Attenuates Macrophage Mobility and Pulmonary Hypertension

Introduction: Hypoxia-inducible factor-1α (HIF-1α) is a regulator of transcription such as energy production in hypoxic cells. But little is known how HIF-1α works in inflammatory cells. Hypothesis: HIF-1α knockout (KO) macrophages impair energy production and suppress development of pulmonary hypertension. Methods: Macrophage and Monocyte specific HIF-1α KO (M-HIF1KO) mice or control mice were used in this experiment. Peritoneal macrophages from M-HIF1KO mice or control mice were incubated under hypoxia (1% O2) or normoxia and assessed ATP production, migratory capacity by migration assay with monocyte chemotactic protein-1 and mRNA expression involved in metabolism and mobility. Next, M-HIF1KO mice or its littermate control mice were put into hypoxia (10% O2) or normoxia for 3 weeks. The mice were assessed hemodynamic status, right ventricular hypertrophy and histology of lung. Results: Macrophages from M-HIF1KO mice produced less ATP compared with control mice in normoxia and hypoxia, and suppressed migration ability significantly. Glucose transporter 1 mRNA, which is involved in energy production especially in hypoxic condition was suppressed significantly in the peritoneal macrophage from M-HIF1KO mice compared with control. In vivo, Control mice in 3 weeks hypoxia manifested significant elevation of right ventricular systolic pressure (RVSP), right ventricular weight / left ventricular and intraventricular septum weight (Fulton index) and percentage of small pulmonary arteries full muscularization. M-HIF1KO mice in hypoxia exhibited a significant reduction in all of these compared with control mice in hypoxia. Macrophage infiltration into right ventricle and lung tissue around pulmonary arteries was also upregulated by hypoxia in control mice, but the hypoxia-induced macrophage infiltration was suppressed in M-HIF1KO mice. Conclusions: Macrophages without HIF-1α impaired glucose transporter 1 mRNA expression, energy production and migration, which relates macrophage infiltration to pulmonary arteries and vascular remodeling in pulmonary hypertension. Macrophage and Monocyte specific HIF-1α inhibition may be the new therapeutic target to pulmonary hypertension.