This is a summary of Asare, Yaw et al. (2025). A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis as published in Immunity. doi.org/10.1016/j.immuni.2025.01.003
The challenge
Despite the success of lipid-lowering therapies and other measures to reduce the complications of atherosclerosis, cardiovascular disease continues to be the leading cause of death globally. Genome-wide association studies by us and other have shown that common genetic variants in a cis-regulatory element (CRE) at histone deacetylase (HDAC)9 are a major risk factor for cardiovascular disease. We, therefore, investigated how HDAC9 contributes to vascular inflammation, specifically examining the effects of CRE-driven HDAC9 expression on atherosclerosis.
Our approach
We utilized mouse models of atherosclerosis to investigate the mechanisms that connect genetic risk variants at HDAC9 to chronic vascular inflammation. We used mice with a deletion of the conserved (CRE) and crossbred them with Apoe−/− mice. We then assessed the effects on both spontaneous and diet-induced atherosclerosis.
Our findings
We discovered that HDAC9 directly interacts with the inflammasome, playing a crucial role in regulating chronic inflammation in atherosclerosis. Our research showed that deleting the conserved non-coding CRE 3' at HDAC9 led to an increase in Hdac9 expression in myeloid cells, which worsened atherosclerosis. Additionally, Hdac9 was found to bind to and mediate the deacetylation of the protein NLRP3, triggering inflammasome activation and pyroptotic cell death. Ultimately, both genetic and pharmacological inhibition of HDAC9 in myeloid cells stabilized atherosclerotic plaques by reducing the expansion of the necrotic core.
The implications
Our findings offer a blueprint for future precision medicine strategies that target individual HDACs and specific cell populations, while preserving the potentially protective effects of HDAC9. This paves the way for a new category of immuno-therapeutics aimed at treating vascular disease. Our approach could be extended to other conditions, given the central role of chronic inflammation in the pathogenesis of a wide range of diseases and the need for targeted anti-inflammatory therapies
Creating SyNergies
The study was led by SyNergy member Martin Dichgans and included our members Arthur Liesz, Christian Weber, Wolfgang Wurst,and Jürgen Bernhagen. We are pursuing HDAC9 as a therapeutic target via SyNergy’s pipeline for clinical translation.
