Ekaterina Legchenko, Philippe Chouvarine, Fatimunnisa Qadri, Edgar Specker, Marc Nazaré, Radoslaw Wesolowski, Susann Matthes, Michael Bader, Georg Hansmann
Hannover Medical School. Max-Delbrück-Center for Molecular Medicine. Trypto Therapeutics GmbH. German Center for Cardiovascular Research. Charité Universitätsmedizin Berlin. University of Lübeck. Friedrich-Alexander-University Erlangen-Nürnberg.
Germany
Journal of the Amerian College of Cardiology Basic to Translational Science
JACC Basi Transl Sci 2024; 9: 890-902
DOI: 10.1016/j.jacbts.2024.04.006
Abstract
The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)-a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3+ T cells and proinflammatory F4/80+ and CD68+ macrophages and proliferating cell nuclear antigen-positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Medical Therapy. Efficacy or Lack of Efficacy
Pulmonary Vascular Pathology
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