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

作者：Zongye Cai, Ly Tu, Siyu Tian, Lin Deng, Yahong Fu, Carole Phan, Thierry van den Bosch, Karin Tran‐Lundmark, Bence Nagy, Horst Olschewski, Xiaoxuan Li, Sihao Wang, Danan Wang, Yi Yan, Lijun Fu, Karin A. Boomars, Christophe Guignabert, Daphne Merkus · 发表于：Journal of the American Heart Association · 年份：2025 · DOI：10.1161/jaha.124.040896 · 被引用次数：9 · 研究领域：Pulmonary Hypertension Research and Treatments、Tryptophan and brain disorders、Phosphodiesterase function and regulation

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 inhibit...