NMN protects vascular endothelial cells from M1 macrophage-derived IL-1β-induced hyperpermeability by inhibiting VE-cadherin degradation.

Katayoshi T, Nakajo T, Kitajima N, Naka W, Kamei Y, Fushimi T, Kageyama M, Akagawa M, Tsuji K

Frontiers in cardiovascular medicine18 May 2026

PMID42232307PMCIDPMC13222840DOI10.3389/fcvm.2026.1748872PepBankPUB-42232307

Summary

Background and aimsVascular endothelial (VE) dysfunction, particularly endothelial hyperpermeability, is a critical pathological process in various inflammatory vascular diseases, including atherosclerosis, vasculitis, and sepsis. Nicotinamide mononucleotide (NMN), an NAD⁺ precursor, has shown anti-inflammatory and vascular protective effects in preclinical models. However, the mechanisms by which NMN preserves endothelial barrier integrity against macrophage-derived inflammatory stimuli remain unclear. This study examined the potential protective role of NMN in endothelial hyperpermeability induced by pro-inflammatory macrophages.MethodsA three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments. Endothelial permeability was evaluated by measuring fluorescently labelled dextran and LDL passages from the luminal (top) to the abluminal side (bottom) of the insert.ResultsM1 macrophage co-culture increased HUVEC permeability, and NMN pretreatment attenuated this hyperpermeability. Mechanistic analysis revealed that interleukin-1β (IL-1β) released by M1 macrophages was the primary contributor to endothelial hyperpermeability. NMN suppressed IL-1β-induced cell-cell gap formation and VE-cadherin degradation in HUVECs by inhibiting nuclear factor kappa B (NF-κB) pathway activation. These findings indicate that NMN prevents IL-1β-induced NF-κB activation and subsequent VE-cadherin degradation, thereby protecting against endothelial hyperpermeability caused by intercellular gap formation. Other NAD⁺ precursors, including nicotinamide riboside, similarly protected against IL-1β-induced hyperpermeability and VE-cadherin degradation. Alternatively, the NAD⁺-dependent deacetylase sirtuin 1 (SIRT1) inhibitor EX527 or SIRT1 siRNA knockdown abrogated NMN-mediated suppression of hyperpermeability and VE-cadherin degradation. Therefore, the protective effect of NMN against IL-1β-mediated endothelial dysfunction is dependent on the NAD⁺ -SIRT1 axis.ConclusionsThis in vitro mechanistic study suggests that the NAD⁺-SIRT1 axis contributes to IL-1β-induced endothelial barrier disruption, supporting further investigation of NMN in inflammatory vascular diseases.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

5 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Mechanism
In HUVECs, NMN pretreatment attenuated hyperpermeability induced by M1 macrophage co-culture.
In plain wordsIn cells, NMN pretreatment reduced excess permeability caused by inflammatory macrophages.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseMacrophage-induced hyperpermeability
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Vascular function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
M1 macrophage co-culture increased HUVEC permeability, and NMN pretreatment attenuated this hyperpermeability.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
Show in the study text Report a problemFND-4223230701
02LabIn vitro (cells)Mechanism
In HUVECs, NMN suppressed IL-1β-induced cell-cell gap formation.
In plain wordsIn cells, NMN reduced gaps between cells caused by IL-1β.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseCell-cell gap formation
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Vascular function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
NMN suppressed IL-1β-induced cell-cell gap formation and VE-cadherin degradation in HUVECs by inhibiting nuclear factor kappa B (NF-κB) pathway activation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
Show in the study text Report a problemFND-4223230702
03LabIn vitro (cells)Mechanism
In HUVECs, NMN suppressed IL-1β-induced VE-cadherin degradation.
In plain wordsIn cells, NMN reduced VE-cadherin breakdown caused by IL-1β.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseVE-cadherin degradation
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Vascular function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
NMN suppressed IL-1β-induced cell-cell gap formation and VE-cadherin degradation in HUVECs by inhibiting nuclear factor kappa B (NF-κB) pathway activation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
Show in the study text Report a problemFND-4223230703
04LabIn vitro (cells)Mechanism
In HUVECs, NMN inhibited IL-1β-induced NF-κB pathway activation.
In plain wordsIn cells, NMN reduced IL-1β-induced activation of the NF-κB pathway.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseNF-κB pathway activation
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
NMN suppressed IL-1β-induced cell-cell gap formation and VE-cadherin degradation in HUVECs by inhibiting nuclear factor kappa B (NF-κB) pathway activation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
Show in the study text Report a problemFND-4223230704
05LabIn vitro (cells)Mechanism
In HUVECs, NMN protected against IL-1β-induced endothelial hyperpermeability.
In plain wordsIn cells, NMN reduced excess endothelial permeability caused by IL-1β.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseIL-1β-induced endothelial hyperpermeability
Study
humann: not reported in source
IL-1β-exposed HUVECs
Outcome group
Vascular function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
These findings indicate that NMN prevents IL-1β-induced NF-κB activation and subsequent VE-cadherin degradation, thereby protecting against endothelial hyperpermeability caused by intercellular gap formation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
Show in the study text Report a problemFND-4223230707

Studies that did not test the peptide alone2

In this study, NMN (nicotinamide mononucleotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking NMN (nicotinamide mononucleotide).

06LabNot a test of NMN (nicotinamide mononucleotide) aloneIn vitro (cells)Mechanism
In HUVECs, SIRT1 inhibition or knockdown abolished NMN-mediated suppression of hyperpermeability.
In plain wordsIn cells, SIRT1 inhibition or gene suppression abolished NMN's protection against excess permeability.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
IncreaseSIRT1-dependent hyperpermeability protection
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Vascular function · Cardiovascular
Source sentences
Summary
Alternatively, the NAD⁺-dependent deacetylase sirtuin 1 (SIRT1) inhibitor EX527 or SIRT1 siRNA knockdown abrogated NMN-mediated suppression of hyperpermeability and VE-cadherin degradation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
In this study, NMN (nicotinamide mononucleotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking NMN (nicotinamide mononucleotide).
Show in the study text Report a problemFND-4223230705
07LabNot a test of NMN (nicotinamide mononucleotide) aloneIn vitro (cells)Mechanism
In HUVECs, SIRT1 inhibition or knockdown abolished NMN-mediated suppression of VE-cadherin degradation.
In plain wordsIn cells, SIRT1 inhibition or gene suppression abolished NMN's protection against VE-cadherin breakdown.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
IncreaseSIRT1-dependent VE-cadherin protection
Study
humann: not reported in source
HUVECs with inflammatory macrophage or IL-1β exposure
Outcome group
Vascular function · Cardiovascular
Source sentences
Summary
Alternatively, the NAD⁺-dependent deacetylase sirtuin 1 (SIRT1) inhibitor EX527 or SIRT1 siRNA knockdown abrogated NMN-mediated suppression of hyperpermeability and VE-cadherin degradation.
1 context sentence(design, population, supporting numbers)
Summary · context
A three-dimensional co-culture model of human umbilical vein endothelial cells (HUVECs) and M1 macrophages was constructed to reproduce inflammatory vascular microenvironments.
In this study, NMN (nicotinamide mononucleotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking NMN (nicotinamide mononucleotide).
Show in the study text Report a problemFND-4223230706

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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