Key result
Pharmacological inhibition of HDAC9 with TMP195 attenuated atherosclerotic lesion formation, reduced inflammatory cell infiltration, and enhanced plaque stability.
Why the study?
Genome-wide association studies identified a prominent role of HDAC9 in atherosclerosis and clinical complications, but the mechanisms linking HDAC9 to these pathologies and its therapeutic potential remained unknown.
Does HDAC9 inhibition reduce atherosclerotic plaque vulnerability and inflammation in preclinical models and patient-derived monocytes?
Does HDAC9 inhibition reduce atherosclerotic plaque vulnerability and inflammation in preclinical models and patient-derived monocytes?
HDAC9 inhibition with TMP195 promotes atherosclerotic plaque stability and reduces vascular inflammation by preventing IKK activation, highlighting a potential therapeutic target for atherosclerosis.
RATIONALE: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction. OBJECTIVE: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. METHODS AND RESULTS: deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6. CONCLUSIONS: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.
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Asare et al. (2020) studied Atherosclerosis. TMP195 (HDAC9 inhibitor) was evaluated on Atherosclerotic plaque stability and inflammatory responses. Pharmacological inhibition of HDAC9 with TMP195 attenuated atherosclerotic lesion formation, reduced inflammatory cell infiltration, and enhanced plaque stability.
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