Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb

Area of Science:

• Cardiovascular Research
• Immunology
• Molecular Biology

Background:

• Pulmonary arterial hypertension (PAH) involves vascular remodeling and right ventricular dysfunction, with limited treatment options.
• Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) acts as a damage-associated molecular pattern protein, contributing to PAH via Toll-like receptor 4 (TLR4) activation.

Purpose of the Study:

• To investigate the role of endothelial cell-specific eNAMPT in experimental pulmonary hypertension (PH).
• To evaluate an eNAMPT-neutralizing monoclonal antibody (mAb) as a therapeutic strategy for reversing established PH.

Main Methods:

• Utilized rat models of PH induced by hypoxia/Sugen and C57BL/6J mice exposed to hypoxia.
• Administered eNAMPT-neutralizing mAb in rats and analyzed endothelial cell-specific eNAMPT knockout (KO) mice.
• Performed hemodynamic, echocardiographic, tissue analyses, biochemical assays, and RNA sequencing on lung tissues and peripheral blood mononuclear cells (PBMCs).

Main Results:

• Hypoxia/Sugen-induced PH in rats showed severe vascular remodeling and elevated right ventricular systolic pressure, significantly attenuated by eNAMPT mAb treatment.
• Plasma levels of eNAMPT, IL-6, and TNF-α were reduced by eNAMPT mAb neutralization.
• Endothelial cell-specific eNAMPT KO mice exhibited reduced PH severity and less endothelial-to-mesenchymal transition (EndMT) compared to wild-type mice.
• eNAMPT mAb treatment rectified dysregulated inflammatory pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs.

Conclusions:

• Endothelial cell-derived eNAMPT is a critical factor in PAH pathogenesis.
• The eNAMPT/TLR4 inflammatory pathway represents a druggable target for reducing PH severity and potentially reversing PAH.