INO80E protects endothelial cells from ox-LDL-induced apoptosis, at least in part by promoting HDAC1-associated YY1 deacetylation and stabilization, suggesting the INO80E-HDAC1-YY1 pathway may represent a candidate protective mechanism in atherosclerosis.
Key Findings
Results
INO80E expression was reduced in atherosclerotic vascular tissue and ox-LDL-treated endothelial cells.
INO80E expression was reduced in the endothelial layer of ApoE-/- aortas, an established mouse model of atherosclerosis.
INO80E expression was also reduced in ox-LDL-treated HUVECs (human umbilical vein endothelial cells) used as an in vitro model of endothelial injury.
These observations suggest that downregulation of INO80E is associated with atherosclerosis-related endothelial injury.
Results
INO80E overexpression attenuated ox-LDL-induced endothelial apoptosis and increased the Bcl-2/BAX ratio.
Lentiviral overexpression of INO80E was used to assess gain-of-function effects in ox-LDL-treated HUVECs.
Apoptosis was measured by flow cytometry and TUNEL staining.
INO80E overexpression attenuated ox-LDL-induced apoptosis and increased the Bcl-2/BAX ratio, indicating a shift toward cell survival.
INO80E knockdown via siRNA produced the opposite effect, increasing apoptosis and reducing the Bcl-2/BAX ratio.
Results
INO80E colocalized with HDAC1 and increased the association between HDAC1 and the transcription factor YY1.
Co-immunoprecipitation and immunofluorescence experiments were used to assess protein-protein interactions and colocalization.
INO80E colocalized with HDAC1 within endothelial cells.
INO80E overexpression increased the HDAC1-YY1 association, facilitating recruitment of the deacetylase to YY1.
Results
INO80E decreased YY1 acetylation and prolonged YY1 protein stability.
YY1 acetylation analysis demonstrated that INO80E overexpression decreased the acetylation level of YY1.
Reduced acetylation was associated with prolonged YY1 protein stability, suggesting that deacetylation protects YY1 from degradation.
These mechanistic findings link INO80E's chromatin-remodeling function to post-translational regulation of YY1.
Results
Pharmacological inhibition of HDAC activity with trichostatin A (TSA) weakened the anti-apoptotic phenotype associated with INO80E overexpression.
TSA, a pan-HDAC inhibitor, was used to pharmacologically block HDAC activity in INO80E-overexpressing cells.
TSA treatment weakened the anti-apoptotic phenotype associated with INO80E overexpression, implicating HDAC activity as necessary for INO80E's protective effect.
This finding supports the mechanistic role of HDAC1-mediated deacetylation downstream of INO80E.
Results
YY1 knockdown partially reversed the regulatory effects of INO80E overexpression on Bcl-2 and BAX expression.
YY1-silencing rescue experiments were performed in INO80E-overexpressing cells to determine whether YY1 mediates INO80E's protective effects.
YY1 knockdown partially reversed the INO80E overexpression-associated regulation of Bcl-2 and BAX.
The partial, rather than complete, reversal suggests that YY1 is a contributor to INO80E's anti-apoptotic function but that additional mechanisms may also be involved.
Conclusions
The authors propose that the INO80E-HDAC1-YY1 pathway represents a candidate protective mechanism in atherosclerosis.
INO80E is a subunit of the INO80 chromatin-remodeling complex, a novel context for regulating endothelial apoptosis in atherosclerosis.
The proposed mechanism involves INO80E facilitating HDAC1 interaction with YY1, leading to YY1 deacetylation, stabilization, and downstream regulation of apoptosis-related genes Bcl-2 and BAX.
The authors note this pathway 'may represent a candidate protective mechanism in AS that requires further validation,' indicating the findings are preliminary and mechanistic.
What This Means
This research suggests that a protein called INO80E, which helps regulate how DNA is packaged inside cells, plays a protective role in the blood vessel lining (endothelium) during atherosclerosis—the buildup of plaques in arteries. The researchers found that INO80E levels drop in diseased arteries of atherosclerosis-prone mice and in lab-grown human endothelial cells exposed to oxidized LDL (a harmful form of cholesterol associated with arterial damage). When they artificially increased INO80E in these cells, the cells were less likely to undergo programmed cell death (apoptosis), and when they reduced INO80E, cell death increased.
The study also mapped out how INO80E appears to work at the molecular level. INO80E interacts with another protein called HDAC1, an enzyme that removes chemical tags (called acetyl groups) from proteins. By bringing HDAC1 closer to a transcription factor called YY1—a protein that regulates gene activity—INO80E promotes the removal of these acetyl tags from YY1, which makes YY1 more stable and longer-lasting inside the cell. A more stable YY1 then appears to influence the balance of proteins that either promote or prevent cell death (Bcl-2 and BAX). When the researchers blocked HDAC activity with a drug or silenced YY1 directly, the protective effects of INO80E were diminished, confirming that this chain of molecular events is important.
This research suggests that the INO80E-HDAC1-YY1 signaling pathway may be a previously unrecognized protective mechanism in the vascular injury that underlies atherosclerosis. The findings are preliminary and mechanistic in nature, conducted in cell culture and mouse models, and the authors themselves note that further validation is needed. Still, identifying this pathway opens potential new avenues for understanding how chromatin-remodeling proteins contribute to cardiovascular disease at the cellular level.
Liu T, Luo Q, Yang S, Yang D, Lv X, Zhao L, et al.. (2026). INO80E Suppresses Oxidized LDL-Induced Endothelial Apoptosis Through HDAC1-Mediated Stabilization of YY1.. Biomolecules. https://doi.org/10.3390/biom16081174