Exploring the Role of Hypusine Signaling in Vascular Smooth Muscle Cells for Mitigating Restenosis in Coronary Artery Disease
Notice bibliographique
Résumé
ABSTRACT Background Post-surgical restenosis in patients with coronary artery disease (CAD) is a pathological vascular remodeling process characterized by neointimal hyperplasia, mainly driven by vascular smooth muscle cells (VSMCs) phenotypic switching toward synthetic and proliferative state. This study identifies novel signaling pathway promoting pro-proliferative phenotype of VSMC and contributing to the neointimal hyperplasia development. Methods The expression of hypusine signaling components was evaluated in human primary culture of coronary artery smooth muscle cells (CoASMCs) isolated from controls and patients with CAD, using comparative proteomic analysis and western blotting, as well as in three preclinical animal models of restenosis; rat carotid injury, mice carotid ligation and canine coronary artery bypass graft. CAD-CoASMCs proliferation was assessed by western blot and immunofluorescence with pharmacological (GC7) and molecular (shRNA) inhibitors of deoxyhypusine synthase (DHPS). The contribution of hypusine signaling to neointimal hyperplasia was investigated using both pharmacological and smooth muscle cell-specific knockout mice approaches. Additionally, human saphenous vein and human coronary artery tissue cultures were employed to explore the translational potential of targeting hypusine signaling to prevent neointimal hyperplasia. Results All components of the hypusine pathway (eukaryote translational initiation factor 5A (eIF5A), deoxyhypusine hydroxylase (DOHH) and DHPS) were significantly overexpressed in CAD-CoASMCs and in preclinical animal models of restenosis. Pharmacological and molecular inhibition of DHPS reduced eIF5A hypusination, VSMC proliferation and expression of extracellular matrix proteins. Proteomic and KEGG analyses demonstrated disruption of cell cycle and DNA replication pathways, including a downregulation of threonine tyrosine kinase (TTK). Our findings suggest that TTK acts as a downstream effector of hypusine signaling, partly mediating to the proliferative effects observed in CAD-CoASMCs. In vivo , pharmacological and genetic inhibition of DHPS significantly reduced neointimal hyperplasia without adverse effects. Finally, ex vivo human tissue culture confirmed that GC7 mitigates growth factor–induced vascular remodeling. Conclusions Hypusine signaling is a critical regulator of VSMC proliferation for neointimal hyperplasia. Inhibiting DHPS reduces vascular remodeling, making it a promising target for preventing restenosis after coronary interventions. Clinical Perspective What Is New? Hypusine signaling is markedly upregulated in coronary artery smooth muscle cells (CoASMCs) from patients with coronary artery disease (CAD) and in multiple preclinical models of restenosis. Proteomic profiling identifies DHPS, the rate-limiting enzyme for eIF5A hypusination, as a key driver of vascular smooth muscle cell (VSMC) pro-proliferative phenotype and extracellular matrix production. Pharmacological (GC7) and genetic inhibition of DHPS effectively suppress eIF5A hypusination, attenuate the synthetic and proliferative CAD-CoASMCs phenotype, and significantly reduce neointimal hyperplasia in rodent models of vascular injury. Ex vivo human tissue demonstrates that DHPS inhibition prevents neointimal hyperplasia, providing strong translational evidence. What Are the Clinical Implications? These findings establish hypusine signaling as a previously unrecognized regulator of pathological VSMC activation in CAD and restenosis. DHPS inhibition emerges as a promising therapeutic strategy to prevent neointimal hyperplasia following coronary interventions such as angioplasty, stenting, or bypass grafting. Collectively, our data support the clinical development of selective DHPS inhibitors as a novel class of therapeutics to improve long-term outcomes after coronary revascularization and potentially other occlusive vascular diseases.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».