Abstract 18333: Tdag51 Deficiency Protects Against Aortic Vascular Calcification by Attenuating Smooth Muscle Cell Death and Osteoblastic Trans-Differentiation
Bibliographic record
Abstract
Vascular Calcification (VC), a severe complication increasing the risk of cardiovascular (CV) mortality and morbidity in ageing, diabetic and chronic renal failure patients. VC occurs as vascular smooth muscle cells (VSMC) differentiate into osteoblast- like cells or undergoing apoptosis, resulting in arterial stiffness, elevated pulse pressure (PP) and left ventricular hypertrophy. Yet, molecular mechanisms modulating VSMC differentiation and viability are unclear. Our previous findings demonstrate that T-cell death associated gene 51 (TDAG51, pleckstrin homology-like domain family member) deficiency protects against atherosclerotic lesions. This study provides evidence that TDAG51 contributes to VC by regulating osteogenic transcription factor RUNX2 expression and VSMC survival. To study aortic calcification (AC), male C57Bl/6 wild-type (TDAG51+/+) and TDAG51 deficient (TDAG51-/-) mice were injected subcutaneously with Vitamin D3 (VD3, 50,000 IU/kg) or vehicle (0.9% Saline) for 10 days, an established model of VC. AC was assessed by plasma Pi and Ca2+ levels and aortic valve, thoracic and abdominal aorta segments stained with von Kossa. Osteogenic differentiation and TDAG51 levels were assessed by immunoblot, qRT-PCR and immunohistochemistry. TDAG51-/- mice are protected against osteogenic differentiation in aortic artery. Hallmark features of VC including elastinolysis, collagen deposition and RUNX2 expression were significantly reduced in TDAG51-/- mice compared to control. TDAG51-/- mice maintained PP levels. Microarray analysis revealed ENPP1 (inhibitor of VC) was increased 15-fold in cultured TDAG51-/- aortic smc. The results were verified by qRT-PCR and immunoblots showing elevated ENPP1 expression in TDAG51-/- in presence or absence of VD3 compared to control. Also plasma pyrophosphate remained elevated in TDAG51-/- mice in presence of VD3, indicating increased endogenous ENPP1 activity. ENPP1 transient knockdown in TDAG51-/- vsmc lead to VC, elevated RUNX2, alkaline phosphatase activity and apoptosis. Our data demonstrate TDAG51 is a novel and key promoter of VC by regulating RUNX2 and ENPP1 levels in VC. TDAG51 loss confers protection against VC, apoptosis and PP elevation thereby reducing CV injury risk.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".