Exploring the Role of Hypusine Signaling in Vascular Smooth Muscle Cells for Mitigating Restenosis in Coronary Artery Disease
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".