IDO‐1 Promotes Pulmonary Vascular Remodeling Via Kynurenine Pathway in Pulmonary Arterial Hypertension

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Background Activation of the plasma kynurenine pathway (KP) may contribute to the progression of pulmonary arterial hypertension (PAH). We investigated the functional role and molecular mechanisms of KP activation in PAH. Methods KP activity was measured in the lungs and plasma of humans and rodents with pulmonary hypertension (PH). KP activity was modulated in lung microvascular endothelial cells in vitro, and through daily oral administration of epacadostat, an inhibitor of IDO‐1 (indoleamine 2,3‐dioxygenase), the rate‐limiting enzyme of the KP, in rats with monocrotaline‐induced PH. Results IDO‐1 expression was increased in peripheral blood mononuclear cells but not in lung tissue of patients with PAH and in rats with monocrotaline‐induced PH. Epacadostat prevented KP activation and the development of monocrotaline‐induced PH, significantly reduced right ventricular systolic pressure (58±9 versus 42±4 and 46±6 mm Hg for placebo versus epacadostat 50 and 100 mg/kg, respectively, P <0.001), pulmonary arterial remodeling (wall thickness, 64±3 versus 58±3 and 58±3%, P <0.001), perivascular inflammation, and right ventricular remodeling (Fulton index, 0.49±0.05 versus 0.36±0.06 and 0.39±0.04, P <0.001). IDO‐1 overexpression contributed to KP activation and de novo nicotinamide adenine dinucleotide + synthesis, increased mitochondrial membrane potential, and endothelial cell proliferation. Inhibition of IDO‐1 using siRNA or epacadostat reversed these effects and inhibited the inflammatory response. Conclusions Increased IDO‐1 expression in peripheral blood mononuclear cells may drive KP activation and promote pulmonary vascular remodeling in PAH. Epacadostat prevents the development of monocrotaline‐induced PH. These findings suggest a novel approach for the treatment of PAH.

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