Signaling Mechanisms Mediating Uridine Adenosine Tetraphosphate–induced Proliferation of Human Vascular Smooth Muscle Cells
Bibliographic record
Abstract
Proliferation of vascular smooth muscle cells (SMCs) plays an important role in the development of atherosclerosis and restenosis. Extracellular mononucleotides, such as adenosine triphosphate and uridine-5'-triphosphate stimulate SMC proliferation. However, the effects of dinucleotides on SMC proliferation and their underlying signaling mechanisms are less well defined. Recently, increasing evidence suggests that the dinucleotide, uridine adenosine tetraphosphate (Up4A) plays a role in the regulation of cardiovascular function. We have previously demonstrated that Up4A stimulates DNA synthesis and proliferation of human SMCs. This study investigated the signaling mechanisms underlying the proliferative effect of Up4A. Up4A-induced increase in bromodeoxyuridine incorporation was blocked by the mammalian target of rapamycin inhibitor, rapamycin, and the MEK inhibitor, PD98059. Up4A-stimulated phosphorylation and kinase activity of S6 kinase (S6K) and Erk1/2 were inhibited by PD98059, whereas phosphorylation and kinase activity of S6K, but not Erk1/2, were inhibited by rapamycin. Up4A also increased the phosphorylation of Akt, which was blocked by the PI3-kinase inhibitor, LY294002. Up4A-stimulated activation of S6K, but not Erk1/2, was also prevented by LY294002. Furthermore, Up4A-stimulated phosphorylation and kinase activity of S6K and Erk1/2 were inhibited by the P2 receptor antagonist, suramin, but not by the P2X receptor antagonist, Ip5I. Up4A also stimulated an increase in the protein expression of cycle-dependent kinase 2, which was prevented by rapamycin, PD98059, and suramin. These results suggest that the signaling mechanisms underlying the Up4A-stimulated proliferation of SMCs are mediated by P2Y receptors and involve the PI3-K/Akt and mitogen-activated protein kinase pathways, leading to the independent activation of S6K and an increase in cycle-dependent kinase 2 expression. This work stresses the concept that dinucleotides, like mononucleotides, play potentially important roles in the regulation of vascular function.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".