Zongye Cai, Ly Tu, Siyu Tian, Lin Deng, Yahong Fu, Carole Phan, Thierry P. P. van den Bosch, Karin Tran‐Lundmark, Bence M. Nagy, Horst Olschewski, Xiaoxuan Li, Sihao Wang, Danan Wang, Yi Yan, Lijun Fu, Karin A. Boomars, Christophe Guignabert, Daphne Merkus
Second Affiliated Hospital and Zhejiang University School of Medicine. Erasmus MC and University Medical Center. Pathophysiologie et Innovation Thérapeutique (HPPIT) and Université Paris-Saclay, School of Medicine. Eighth Affiliated Hospital of Sun Yat-sen University. Lund University and Skane University Hospital. Medical University of Graz. Charite University Medicine. Sigmund Freud Private University. Shanghai Children’s Medical Center and Jiao Tong University. University Clinic Munich, LMU Munich and German Center for Cardiovascular Research (DZHK).
China, Netherlands, France, Sweden, Austria and Germany
Journal of the American Heart Association
J Am Heart Assoc 2025;
DOI: 10.1161/JAHA.124.040896
Abstract
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.
Category
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class I. Pulmonary Hypertension Associated with Inflammation
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes