AT1 receptor activation of vascular smooth muscle cell ERK1/2 and p38 map kinase is differentially regulated in genetic hypertension
Bibliographic record
Abstract
Extracellular signal-activated kinases (ERK1/2) and p38 have been implicated in pathological processes underlying vascular remodeling in hypertension. We investigated the role of ERK1/2 and p38 in vascular growth effects mediated by Ang II in SHR. Vascular smooth muscle cells (VSMC) from WKY and SHR were studied. Ang II-induced phosphorylation of ERK1/2 and p38 were assessed by Western blots assays. c-fos mRNA expression was determined by RT-PCR. Ang II-stimulated DNA and protein synthesis were assessed by measuring incorporation of 3H-thymidine and 3H-leucine respectively. Ang II increased phosphorylation of ERK1/2 and p38. Responses were significantly increased 3–4 fold in SHR compared with WKY. PD98059, the selective MEK1/2 inhibitor, and SB202190, the selective p38 inhibitor, abolished Ang II-induced ERK1/2 and p38 activation respectively. Ang II increased (p < 0.05) c-fos mRNA expression in SHR (173 ± 12%) and had a small stimulatory effect in WKY (119 ± 6%). These actions were inhibited by PD98059, but not by SB202190. Ang II dose-dependently increased 3H-thymidine and 3H-leucine incorporation. Responses were enhanced (p < 0.02) in SHR. Pretreatment of cells with PD98059 attenuated Ang II-induced growth effects and normalized responses in SHR. SB212190 did not alter DNA synthesis, but significantly reduced (P < 0.05) protein synthesis in SHR (232 ± 12 vs 132 ± 117%). Ang II-stimulated effects were inhibited by irbesartan, AT1 receptor antagonist, but not by PD123319, AT2 receptor blocker. Thus Ang II-mediated activation of vascular ERK1/2 and p38 is increased in SHR. Augmented c-fos and growth responses are generated primarily via ERK1/2. p38 influences Ang II-induced hypertrophy in SHR but not in WKY. These results indicate differential roles of ERK1/2 and p38 in AT1-stimulated VSMC growth, which may contribute to vascular remodeling in genetic hypertension. (Supported by Bristol-Myers Squibb/Sanofi)
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.000 |
| 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".