Abstract 482: A Novel Small Molecule Inhibitor of Acetyltransferase p300 Ameliorates Hypertension-Induced Cardiac and Renal Fibrosis
Bibliographic record
Abstract
Rationale: Fibrosis is a common pathophysiological manifestation of chronically injured or stress-affected organs. Additionally, cardiac and renal fibrosis remain leading causes of global morbidity and mortality. Meanwhile, no effective therapy is available to halt the onset and progression of cardiac and renal fibrogenesis. We have previously demonstrated that p300 with intrinsic factor acetyltransferase (FATp300) activity is an essential epigenetic regulator of profibrogenic signal-induced matrix protein synthesis. Objective: Here, we attempted to delineate the therapeutic efficacy of a small molecule inhibitor of FATp300, L002, in blocking i) TGF-b-induced profibrogenic processes in cardiac and renal cells in vitro, and ii) Angiotensin II-induced cardiac and renal fibrogenesis in mice. Methods and Results: Analysis of cardiac and renal cells demonstrates that L002 inhibits specific histone acetylation and blunts TGF-b induced profibrogenic processes, including cellular proliferation, migration, myofibroblast differentiation and extracellular matrix protein synthesis. The mRNA analysis further indicates that matrix protein, collagen, and myofibroblast marker, a-SMA are inhibited at the transcriptional level. L002 also prevents TGF-b-induced FATp300 upregulation suggesting that TGF-b-induced FATp300 expression is partly self-regulated. However, TGF-b-induced Smad activation is unaltered in the presence of L002, demonstrating its target specificity. Further, mice infused with Angiotensin II show increased blood pressure, cardiac hypertrophy and increased heart weight. Conversely, co-administration of L002 reduces Angiotensin II-induced cardiac hypertrophy and left ventricular wall thickness. Most importantly, L002 administration ameliorates Angiotensin II-induced cardiac and renal fibrosis in mice. Conclusions: Taken together this study demonstrates that specific pharmacological inhibition of elevated factor acetyltransferase activity of p300, a major epigenetic regulator, is an ideal approach to control hypertension- or other stress-induced cardiac and renal fibrogenesis as seen in a wide variety of cardiovascular and renal diseases.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 |
| 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".