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

Mohamed Ahmed, Nahla Zaghloul, Prisca Zimmerman, Nancy G. Casanova, Xiaoguang Sun, Jin H. Song, Vivian Reyes Hernon, Saad Sammani, Franz Rischard, Olga Rafikova, Ruslan Rafikov, Ayako Makino, Carrie L. Kempf, Sara M. Camp, Jian Wang, Ankit Desai, Yves A Lussier, Jason X.J. Yuan, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPTec−/− mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF-α were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPTec−/− KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.

Original languageEnglish (US)
JournalPulmonary Circulation
Volume11
Issue number4
DOIs
StatePublished - 2021

Keywords

  • 3 terms DEGs
  • Akt/mTOR
  • DAMP
  • NAMPT
  • TLR4

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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