Ang‐II‐Induced Phosphorylation and Nuclear Export of Histone Deacetylase 5 is Mediated by an AKT‐Dependent Pathway in Vascular Smooth Muscle Cells
Bibliographic record
Abstract
Augmented levels of angiotensin‐II (Ang‐II) are associated with the development of cardiovascular disorders such as atherosclerosis and hypertension. Exaggerated activation of Ang‐II‐induced signaling events and expression of genes linked to cell proliferation, hypertrophy and migration have been demonstrated to contribute to the development of these vascular pathologies. Ang‐II induces the phosphorylation of class II histone deacetylases (HDACs), particularly HDAC4 and HDAC5. HDACs regulate gene transcription by their ability to modify the acetylation status of the lysine residues in histone and non‐histone proteins. A heightened activation of HDACs, notably HDAC5, has been associated with vascular disorders such as atherosclerosis. We have shown earlier that Ang‐II induces the expression of early growth response factor‐1 (Egr‐1), a zinc finger transcription factor which is upregulated in atherosclerotic lesions and in animal models of vascular injury. We have also reported that the PI3Kinase/AKT pathway plays a key role in inducing the expression of Egr‐1 in vascular smooth muscle cells (VSMC). However, the role of the AKT pathway in HDAC5 phosphorylation and the contribution of HDAC5 in Egr‐1 expression in VSMC remains unexplored. Here, we show that Ang‐II induced the phosphorylation of HDAC5 in a time and dose‐dependent manner, and pharmacological blockade of the PI3K/AKT pathway by wortmannin or SC66 attenuated Ang‐II‐induced HDAC5 phosphorylation in A10 VSMC. In addition, Ang‐II treatment of VSMC resulted in the translocation of HDAC5 from the nucleus to the cytosol, and the inhibition of AKT by SC66 almost completely attenuated the nuclear export of HDAC5 induced by Ang‐II. In contrast, pharmacological blockade of the MAPK pathway by UO126 was ineffective in reducing Ang‐II‐induced HDAC5 phosphorylation. Furthermore, pharmacological inhibition of HDAC5 by MC1568 or siRNA‐induced silencing of HDAC5 suppressed Ang‐II‐induced Egr‐1 expression. In summary, our results suggest that Ang‐II induces the phosphorylation and nuclear export of HDAC5 via the PI3K/AKT‐dependent signaling pathway and that HDAC5 is an upstream modulator of Egr‐1 expression in VSMC. Support or Funding Information Supported by Canadian Institutes of Health Research This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".