eNAMPT/TLR4 signaling drives PAH cellular phenotypic switching and lung vascular remodeling

Area of Science:

• Pulmonary Hypertension Research
• Vascular Biology
• Immunology

Background:

• Pulmonary arterial hypertension (PAH) vascular remodeling driven by cellular phenotypic switching is a therapeutic challenge.
• Nicotinamide phosphoribosyltransferase (eNAMPT)/Toll-like receptor 4 (TLR4) signaling is implicated in pulmonary hypertension (PH) pathobiology.
• eNAMPT neutralization using ALT-100 mAb was explored in preclinical PH models.

Purpose of the Study:

• To investigate the role of eNAMPT/TLR4 signaling in cellular phenotypic switching in PH.
• To evaluate the therapeutic efficacy of an eNAMPT-neutralizing antibody (ALT-100 mAb) in preclinical PH models.
• To assess the impact of ALT-100 mAb on endothelial cells, smooth muscle cells, and monocytes/macrophages.

Main Methods:

• Preclinical rat models of PH induced by monocrotaline (MCT) or hypoxia/Sugen (Hy/Su) were established.
• Rats received subcutaneous injections of IgG or ALT-100 mAb starting at week 4.
• PH severity was assessed hemodynamically and histologically, with lung tissue analyzed by single-cell RNA sequencing (scRNAseq) at day 42.

Main Results:

• ALT-100 mAb significantly attenuated PH severity, including hemodynamic, histologic, and vascular remodeling indices, in both MCT-PH and Hy/Su-PH rats.
• scRNAseq revealed that Hy/Su exposure promoted endothelial-to-mesenchymal transition (EndMT), smooth muscle cell proliferation, and monocyte differentiation into macrophages.
• Treatment with ALT-100 mAb ameliorated these cellular phenotypic switching events in Hy/Su-PH rats.

Conclusions:

• Autocrine and paracrine eNAMPT/TLR4 signaling drives accelerated cellular phenotypic switching in PH.
• This signaling pathway represents a druggable target for reversing vascular remodeling in PH.
• ALT-100 mAb demonstrated therapeutic potential by mitigating PH and associated cellular changes.