Novel Tryptophan Hydroxylase Inhibitor TPT-001 Reverses Pulmonary Arterial Hypertension, Vascular Remodeling, and Proliferative-Proinflammatory Gene Expression

Background: The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)—a progressive, uncurable disease. Recently, we developed a highly specific inhibitor of the serotonin-synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). Here, we aim to evaluate the treatment mechanisms and efficacy of oral TPHi TPT-001 in the Sugen/hypoxia rat model with severe PAH.

Methods: Male Sprague–Dawley rats were divided into three groups: (i) ConNx, control animals; (ii) SuHx (injected subcutaneously with VEGFR2-inhibitor SU5416 [Sugen], and exposed to chronic hypoxia [3 weeks], followed by 6 weeks of room air); (iii) SuHx + TPHi (SuHx animals treated orally with TPHi for 5 weeks). Closed-chest right–left heart catheterization and echocardiography were performed. Lungs underwent standard histology, immunohistochemistry, and immune fluorescent microscopy, and mRNA-seq analysis.

Results: In comparison with SuHx-exposed rats which developed severe PAH and RV dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic pressure (RVSP; 41 ± 2.3 vs. 86 ± 6.5 mm Hg; p < 0.001; mean ± SEM) and end-diastolic pressures (RVEDP; 4 ± 0.7 vs. 14 ± 1.7 mm Hg; p < 0.001; mean ± SEM), decreased RV hypertrophy and dilation (all not significantly different from controls), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3+ T cells, proinflammatory F4/80+/CD68+ macrophages, and PCNA⁺ alveolar epithelial cells, suppressed by TPHi treatment. Whole lung mRNA-sequencing in SuHx rats unraveled distinct gene expression patterns related to PASMC proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1) which reversed expression upon TPHi treatment.

Conclusion: Inhibition of TPH1 with a new class of drugs (here: oral TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway.

Publikationsverlauf

Artikel online veröffentlicht:
11. Februar 2025