Targeting autophagy to treat neointimal hyperplasia in vascular disease
Open accessAbstract
Runan Yan, Simon Tual-Chalot, Konstantinos Stellos; Targeting autophagy to treat neointimal hyperplasia in vascular disease, Cardiovascular Research, , cva
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Claims the paper makes
20 of 24 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
Autophagy is critical for NRF3-mediated vascular smooth muscle cell proliferation and migration.
“Restoration of NRF3 expression in the vascular wall using an AAV9 delivery system in NRF3 global knockout mice increased the neointimal area, which was prevented by administration of the autophagy inhibitor chloroquine, confirming the critical for autophagy in NRF3-mediated VSMC proliferation and migration 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Premisecitation
NRF3 promotes vascular smooth muscle cell proliferation and migration under atherogenic stress.
“While NRF3 has been shown to promote embryonic stem cell differentiation toward contractile SMCs 9 , it promotes VSMC proliferation and migration under atherogenic stress 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Interpretationcitation
Targeting NRF3 has therapeutic translational relevance for restenosis intervention.
“Finally, moving beyond the murine models, the authors administered AAV9-shNrf3-mediated targeted suppression of NRF3 to a porcine model of carotid artery stenting.They showed decreased neointimal hyperplasia, reduced vascular inflammation, and reduction of TRIM5, thereby demonstrating the therapeutic translational of targeting NRF3 relevance for restenosis intervention 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Rests on an assumption: Findings from murine and porcine models of neointimal hyperplasia are predictive of human disease.
- Premisecitation
Neointimal hyperplasia is driven by pathological alterations in vascular smooth muscle cell function.
“At the cellular level, neointimal hyperplasia is driven by pathological alterations in VSMC function.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [2] Liberale, Roadmap for alleviating the manifestations of ageing in the cardiovascular system, Nat Rev Cardiol source
The Introduction’s ‘Vascular ageing’ section (page unavailable) describes intimal thickening as part of vascular remodelling and reports pathological VSMC changes, including increased proliferation and migration. It does not specifically identify altered VSMC function as the driver of neointimal hyperplasia. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [3] Sachse, 2023, RNA-binding proteins in vascular inflammation and atherosclerosis, Atherosclerosis source
- Premisecitation
Pathological stimuli cause endoplasmic reticulum stress marked by an increase of ATF4.
“Mechanistically, these stimuli caused endoplasmic reticulum stress response marked by an increase of ATF4.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Premisecitation
Autophagy is a critical determinant of vascular smooth muscle cell plasticity and phenotypic switching.
“Indeed, autophagy is a critical determinant of VSMC plasticity and phenotypic switching.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Grootaert, 2018, Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis, Cardiovasc Res source
- Premisecitation
Under stressors such as hypoxia, inflammation, and hemodynamic changes, vascular smooth muscle cells transition from a differentiated contractile phenotype to a synthetic, proliferative state.
“However, under stressors such as hypoxia, inflammation, and hemodynamic changes, VSMCs transition into a synthetic, proliferative state, producing extracellular matrix components, secreting proinflammatory cytokines, recruiting immune cells, and exacerbating vascular inflammation 2 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] Liberale, Roadmap for alleviating the manifestations of ageing in the cardiovascular system, Nat Rev Cardiol source
The Introduction’s “Vascular ageing” section says that immune-cell infiltration can cause VSMCs to switch to a synthetic phenotype with reduced contractile-protein expression and increased proliferation. It also identifies mechanical forces as influences on VSMCs, but does not identify hypoxia as a trigger of this switch; its discussion of hypoxia and haemodynamic stress concerns endothelial cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
NRF3 knockdown decreases proliferation, migration, and inflammatory responses of human and murine vascular smooth muscle cells under PDGF-BB, TNF-α, and ox-LDL pathological stimuli.
“Then, they reported that NRF3 knockdown decreased proliferation, migration, and inflammatory responses of human and murine VSMCs under PDGF-BB, TNF-α, and ox-LDL pathological stimuli.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
The Results section, “Nrf3 promotes proliferation, migration, and inflammatory response of the VSMCs,” reports reduced proliferation and migration under PDGF-BB, TNF-α, and ox-LDL in Nrf3-deficient mouse VSMCs, and similar effects after NRF3 knockdown in human VSMCs. For mouse VSMCs, however, it reports reduced inflammatory markers specifically under TNF-α, not under all three named stimuli; the mouse cells were from knockout animals rather than knockdown experiments. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
NRF3 displays uneven tissue distribution unlike NRF1 and NRF2.
“Unlike its broadly expressed counterparts NRF1 and NRF2, NRF3 displays uneven tissue distribution.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Ibrahim, 2020, Defining the functional targets of cap'n'collar transcription factors NRF1, NRF2, and NRF3, Antioxidants (Basel) source
- Premisecitation
TRIM5 recruits BECN1 and assembles a functional complex to initiate autophagosome formation.
“TRIM5 recruits BECN1 and assembles a functional complex to initiate autophagosome formation.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Premisecitation
Defective autophagy is implicated in the pathogenesis of several vascular diseases.
“Defective autophagy has therefore been implicated in the pathogenesis of several vascular diseases 5 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Grootaert, 2018, Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis, Cardiovasc Res source
- Premisecitation
NRF3 promotes TRIM5/BECN1-induced vascular smooth muscle cell autophagy in response to pathological stimuli or vascular injury.
“ATF4 transcriptionally activates NRF3, triggering its upregulation to induce TRIM5 expression, a recently identified genetic risk locus for coronary artery disease, and promoted TRIM5/BECN1-induced VSMC autophagy in response to pathological stimuli or vascular injury 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
- Interpretationreasoning
The NRF3-TRIM5 axis in regulating autophagy in vascular smooth muscle cells provides a new direction for developing treatments for neointimal hyperplasia-related diseases.
“Overall, the newly discovered NRF3-TRIM5 axis in regulating autophagy in VSMCs provides a new direction for developing treatments for neointimal hyperplasia-related diseases.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from murine and porcine models of neointimal hyperplasia are predictive of human disease.
- Interpretationreasoning
NRF3 has context-dependent and tissue-specific behaviour.
“In that view, NRF3 emerges as an attractive therapeutic target due to its contextdependent and tissue-specific behaviour.”
Quote in the paperSubstantial claim - Interpretationcitation
NRF3 drives disease-related phenotype upon pathological stimulation.
“Similarly, increased NRF3 expression in response to cardiac injury promotes cardiomyocyte apoptosis and contributes to adverse cardiac remodeling 10 , confirming a role for NRF3 in driving disease-related phenotype upon pathological stimulation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Chen, 2025, Nrf3-mediated mitochondrial superoxide promotes cardiomyocyte apoptosis and impairs cardiac functions by suppressing Pitx2, Circulation source
- May combine two claims. 9
- Classified as probably not a substantial claim. 2
May combine two claims.
PremisecitationThis autophagy activation promotes vascular smooth muscle cell phenotypic switching, characterized by enhanced proliferation, migration, and inflammation, ultimately driving neointimal hyperplasia.
“This autophagy activation promotes vascular smooth muscle cell phenotypic switching, characterized by enhanced proliferation, migration, and inflammation, ultimately driving neointimal hyperplasia.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
The Results (pages unavailable) show that Nrf3–Trim5-mediated autophagy promotes VSMC proliferation and migration and contributes to injury-induced neointimal hyperplasia; the Discussion says it mediates VSMC plasticity. The paper also reports an Nrf3-associated inflammatory response, but the passages do not establish that autophagy activation causes that response. The Discussion further cautions that autophagy’s effects on vascular remodelling are context dependent, so the claim is too broad as written. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAAV9-shNrf3-mediated targeted suppression of NRF3 in a porcine model of carotid artery stenting decreases neointimal hyperplasia, reduces vascular inflammation, and reduces TRIM5.
“Finally, moving beyond the murine models, the authors administered AAV9-shNrf3-mediated targeted suppression of NRF3 to a porcine model of carotid artery stenting.They showed decreased neointimal hyperplasia, reduced vascular inflammation, and reduction of TRIM5, thereby demonstrating the therapeutic translational of targeting NRF3 relevance for restenosis intervention 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
May combine two claims.
PremisecitationImpaired or excessive autophagy may lead to cell death, neointimal formation and atherosclerotic plaque instability.
“While physiological autophagy promotes VSMC survival, impaired or excessive autophagy may lead to cell death, neointimal formation and atherosclerotic plaque instability 5 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Grootaert, 2018, Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis, Cardiovasc Res source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNRF3 drives a more selective transcriptional program.
“Moreover, NRF3 drive a more selective transcriptional program 7 , a feature that could potentially reduce off-target effects.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Ibrahim, 2020, Defining the functional targets of cap'n'collar transcription factors NRF1, NRF2, and NRF3, Antioxidants (Basel) source
The Results (§3.2) found that NRF3 overexpression regulated considerably fewer transcripts than NRF1 or NRF2 in HEK293T cells, supporting the comparison. The Discussion (§4) describes this as a suggested smaller program and notes that NRF3 activity may depend on tissue or context; the unqualified claim that NRF3 drives a more selective program is therefore stronger than the finding. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationTargeting autophagy has bidirectional therapeutic potential in vascular pathologies: autophagy induction may protect against endothelial dysfunction and hypertension, while autophagy-inducing stimuli promote vascular smooth muscle cell proliferation leading to vascular remodeling.
“Furthermore, targeting autophagy demonstrates bidirectional therapeutic potential in vascular pathologies.While autophagy induction may protect against endothelial dysfunction and hypertension, autophagy-inducing stimuli promote VSMC proliferation, leading to vascular remodeling.In contrast, rapamycin-based drugs are used to treat arterial stenosis 5 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Grootaert, 2018, Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis, Cardiovasc Res source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIncreased NRF3 expression in human carotid and femoral atherosclerotic lesions is associated with vascular smooth muscle cell phenotypic switch to a synthetic and inflammatory phenotype and with the extent of vascular remodeling.
“In the present study, the authors first showed an increased NRF3 expression in both human carotid and femoral atherosclerotic lesions, which was associated with VSMCs phenotypic switch to a synthetic and inflammatory phenotype, and with the extent of vascular remodeling 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
May combine two claims.
PremisecitationATF4 transcriptionally activates NRF3, triggering its upregulation to induce TRIM5 expression.
“ATF4 transcriptionally activates NRF3, triggering its upregulation to induce TRIM5 expression, a recently identified genetic risk locus for coronary artery disease, and promoted TRIM5/BECN1-induced VSMC autophagy in response to pathological stimuli or vascular injury 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
May combine two claims.
PremisecitationRestoration of NRF3 expression in the vascular wall using AAV9 in NRF3 global knockout mice increases neointimal area, which is prevented by chloroquine.
“Restoration of NRF3 expression in the vascular wall using an AAV9 delivery system in NRF3 global knockout mice increased the neointimal area, which was prevented by administration of the autophagy inhibitor chloroquine, confirming the critical for autophagy in NRF3-mediated VSMC proliferation and migration 6 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chen, 2025, Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia, Cardiovasc Res source
May combine two claims.
PremisecitationEnhanced vascular smooth muscle cell proliferative capacity results in vascular wall thickening, luminal stenosis, and progression toward atherosclerosis or arterial restenosis.
“Their enhanced proliferative capacity results in vascular wall thickening, luminal stenosis, and progression toward atherosclerosis, arterial restenosis or vascular lumen narrowing in various vascular beds 3 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Sachse, 2023, RNA-binding proteins in vascular inflammation and atherosclerosis, Atherosclerosis source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIncreased NRF3 expression in response to cardiac injury promotes cardiomyocyte apoptosis and contributes to adverse cardiac remodeling.
“Similarly, increased NRF3 expression in response to cardiac injury promotes cardiomyocyte apoptosis and contributes to adverse cardiac remodeling 10 , confirming a role for NRF3 in driving disease-related phenotype upon pathological stimulation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Chen, 2025, Nrf3-mediated mitochondrial superoxide promotes cardiomyocyte apoptosis and impairs cardiac functions by suppressing Pitx2, Circulation source
The paper relies on this without support.
Findings from murine and porcine models of neointimal hyperplasia are predictive of human disease.
“Finally, moving beyond the murine models, the authors administered AAV9-shNrf3-mediated targeted suppression of NRF3 to a porcine model of carotid artery stenting.They showed decreased neointimal hyperplasia, reduced vascular inflammation, and reduction of TRIM5, thereby demonstrating the therapeutic translational of targeting NRF3 relevance for restenosis intervention 6 .”
Cites
Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles
Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R., & Kroemer, G. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.22 · Cited by 842 · see citing works
Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis
Grootaert, M. O. J., Moulis, M., Roth, L., Martinet, W., Vindis, C., Bennett, M. R., & De Meyer, G. R. Y. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy007 · Cited by 606 · see citing works
Crucial role of nrf3 in smooth muscle cell differentiation from stem cells
Pepe, A. E., Xiao, Q., Zampetaki, A., Zhang, Z., Kobayashi, A., Hu, Y., & Xu, Q. (2010) · Circulation Research · doi:10.1161/circresaha.109.211417 · Cited by 94 · see citing works
Defining the functional targets of cap'n'collar transcription factors NRF1, NRF2, and NRF3
Ibrahim, L., Mesgarzadeh, J., Xu, I., Powers, E. T., Wiseman, R. L., & Bollong, M. J. (2020) · Antioxidants · doi:10.3390/antiox9101025 · Cited by 67 · see citing works
Animal Models of Neointimal Hyperplasia and Restenosis
Ebert, M. L. A., Schmidt, V. F., Pfaff, L., von Thaden, A., Kimm, M. A., & Wildgruber, M. (2021) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2021.06.006 · Cited by 63 · see citing works
Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., et al. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01130-5 · Cited by 59 · see citing works
Self-citationChen, Q., Zheng, A., Xu, X., Shi, Z., Yang, M., Sun, S., Wang, L., Wang, Y., Zhao, H., Xiao, Q., et al. (2025) · Circulation · doi:10.1161/circulationaha.124.070286 · Cited by 54 · see citing works
RNA-binding proteins in vascular inflammation and atherosclerosis
Sachse, M., Tual-Chalot, S., Ciliberti, G., Amponsah-Offeh, M., Stamatelopoulos, K., Gatsiou, A., & Stellos, K. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.01.008 · Cited by 29 · see citing works
Self-citationNRF3 activates mTORC1 arginine-dependently for cancer cell viability
Hirose, S., Waku, T., Tani, M., Masuda, H., Endo, K., Ashitani, S., Aketa, I., Kitano, H., Nakada, S., Wada, A., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106045 · Cited by 15 · see citing works
Chen, Q., Sun, S., Shi, Z., Wang, L., Wang, Y., Zheng, A., Xu, X., Yang, M., Sun, K., Xiao, Q., et al. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf084 · Cited by 5 · see citing works
Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual‐Chalot, S., Sedej, S., et al. (2025) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-281174
Self-citation
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Remuzzi, A., Soliveri, L., Poloni, S., et al. (2026) · Annals of Biomedical Engineering · doi:10.1007/s10439-026-04360-x
- Authors
- Yan, R., Tual-Chalot, S., & Stellos, K.
- Affiliations
- Heidelberg University (DE)
- Faculty of Medical Sciences, Biosciences Institute, Vascular Biology and Medicine Theme, Newcastle University , International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ ,
- Max Delbrück Center (DE)
- Corresponding author
- Stellos, Konstantinos
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-06-20
- Volume
- 121
- Issue
- 8
- Pages
- 1149-1151
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC12310277
- OpenAlex
- W4411721457
- Cited by
- 1
- References
- 11
- Citations by year
- 2026: 1
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- China Scholarship Council
- British Heart Foundation (PG/23/11093)
- Royal Society (RG\R1\241197)
- German Research Foundation (CRC1366 C07)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Coronary Interventions and Diagnostics
- Keywords
- autophagy, intimal hyperplasia, vascular disease, autophagy modulation, vascular remodeling
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