# Novel mechanism for eNAMPT secretion in PAH vascular remodeling

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2023 · $40,103

## Abstract

ABSTRACT
Pulmonary arterial hypertension (PH) is a progressive disease leading to pulmonary vascular remodeling,
increased pulmonary arterial pressures, declining right ventricular (RV) function, right heart failure, and death.
No curative therapies are currently available. In this F31 application, the PI will train in the acclaimed translational
laboratory of Joe GN Garcia, MD and seek to address the unmet need for novel effective PAH therapeutic
strategies by focusing on eNAMPT (extracellular nicotinamide phosphoribosyltransferase). eNAMPT is a novel
damage-associated molecular pattern protein (DAMP) and PAH target identified by the Garcia lab utilizing
genomic–intensive approaches. Intracellular NAMPT mainly serves as a rate-limiting enzyme in nicotinamide
adenine dinucleotide (NAD) synthesis. However, secreted extracellular eNAMPT (from leukocytes, lymphocytes,
endothelium, epithelium) ligates the Toll-like receptor 4 (TLR4) to potently activate this inflammatory signaling
cascade. eNAMPT/TLR4 participation in innate immunity inflammatory responses is key to the severity of several
serious inflammatory disorders (ARDS, lung fibrosis) including PH with elevated plasma eNAMPT levels in PH
subjects correlating with RV dysfunction. Increased eNAMPT secretion is influenced by NAMPT promoter SNPs
and NAMPT transcriptional regulation by anti-oxidant response elements and hypoxia response elements
induced by transcription factors such as HIF-2α. We have demonstrated that the eNAMPT/TLR4 pathway is
highly druggable as a humanized eNAMPT-neutralizing mAb effectively reduced the severity of preclinical PH.
Several key gaps remain, however, in fundamentally understanding the role of eNAMPT in PH pathobiology. For
example, it remains unclear as to whether endothelial cells (ECs) or smooth muscle cells (SMCs) are the primary
target cell for eNAMPT involvement in PH. In Specific Aim #1 (SA), the PI will examine EC- and SMC-specific
NAMPT promoter responses to PAH stimuli that increase NAMPT transcriptional activities and translation. SA
#2 will investigate the EC- and SMC-specific intracellular mechanisms contributing to eNAMPT secretion into
the circulation by PAH stimuli focusing on the role of NAMPT dimerization, inflammasome and ABC transporter
activation and generation of extracellular vesicles. Finally, utilizing human and rodent tissues, SA #3 will define
EC- and SMC-specific eNAMPT-induced responses by examining cytosolic Ca2+ signaling, cell
proliferation/activation, cell survival, EMT activity and angiogenic activity as readouts. Together, these studies
will provide key novel mechanistic insights into eNAMPT’s influence on vascular remodeling and PH
pathobiology.

## Key facts

- **NIH application ID:** 10951663
- **Project number:** 7F31AG082409-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Marisela Rodriguez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,103
- **Award type:** 7
- **Project period:** 2023-08-21 → 2025-08-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951663

## Citation

> US National Institutes of Health, RePORTER application 10951663, Novel mechanism for eNAMPT secretion in PAH vascular remodeling (7F31AG082409-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10951663. Licensed CC0.

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