Abstract 458: Loss of Smooth Muscle α-actin in Mice Results in Thoracic Aortic Aneurysms via Increased Reactive Oxygen Species, Increased Nox4,and Increased Angiotensin II type 1 Receptor-Mediated Signaling
Bibliographic record
Abstract
Objective: ACTA2 mutations cause 10-14% of familial thoracic aortic aneurysms and dissections. Mice deficient in smooth muscle α-actin (Acta2-/-) develop root and ascending thoracic aortic enlargement associated with thickening of the aortic media and fragmentation and disarray of elastic fibers. We hypothesized that blocking AT1 activation would block the aortic pathology and prevent aortic enlargement in Acta2-/- mice. Methods and Results: Beginning at 4 weeks of age, Acta2-/- mice were treated with losartan or placebo (n≥10) for 6 months and echocardiograms were performed at baseline and every other month. The aortic root in Acta2-/- mice was found to undergo progressive dilatation. After 6 months of treatment, there was no difference in the diameter of the aortic root between wild-type (WT) mice and the losartan treated mice (p=0.44). Histologic analysis of Acta2-/- aortas demonstrated medial thickening and fragmentation of elastic fibers which was normalized by treatment with losartan. Gene expression of matrix metalloproteinase-2 and -9 (Mmp2, Mmp9), along with lumican and decorin, interleukin-6 (Il6) and phosphorylation of RelA (a subunit of nuclear factor κB, NF-κB) was increased in Acta2-/- aortas, and was corrected by treatment with losartan. NADPH oxidase 4 and AT1a mRNA was increased in Acta2-/- aortic smooth muscle cells (SMCs) and aortas. Increase of AT1a was blocked by lowering reactive oxygen species (ROS) with N-actetyl cysteine (NAC). Angiotensin II (AngII) dose response studies suggested Acta2-/- aortic SMCs had increased sensitivity to Ang II. Additionally, Acta2-/- SMCs had increased ROS compared to WT by flow cytometry (P<0.05). Increased ROS was also observed in aortic samples derived from Acta2-/- mice. Blocking ROS using NAC attenuated aneurysm formation by reducing the expression of Mmps and IL6 and reducing signaling through AT1 in Acta2-/- mice. Genetic deletion of AT1a attenuated ROS and expression of Mmps and IL6 levels in the Acta2-/-aortas but not to WT levels. Conclusions: Our results demonstrate that complete loss of α-SMA leads to aortic dilation and pathologic changes by increasing SMC ROS levels, thus increasing sensitivity to AngII, which results in NF-κB activation and increased expression of Mmps and IL6.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.011 | 0.003 |
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".