Back to Search
Start Over
Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.
- Source :
-
Circulation research [Circ Res] 2020 Aug 28; Vol. 127 (6), pp. 811-823. Date of Electronic Publication: 2020 Jun 17. - Publication Year :
- 2020
-
Abstract
- 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.<br />Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection.<br />Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 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.<br />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.
- Subjects :
- Acetylation
Aged
Aged, 80 and over
Animals
Arteries drug effects
Arteries pathology
Atherosclerosis drug therapy
Atherosclerosis genetics
Atherosclerosis pathology
CX3C Chemokine Receptor 1 genetics
CX3C Chemokine Receptor 1 metabolism
Cytokines metabolism
Disease Models, Animal
Endothelial Cells enzymology
Endothelial Cells pathology
Enzyme Activation
Female
Fibrosis
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases genetics
Humans
I-kappa B Kinase genetics
Inflammation Mediators metabolism
Leukocyte Rolling
Macrophages enzymology
Macrophages pathology
Male
Mice, Knockout, ApoE
Middle Aged
Monocytes enzymology
Monocytes pathology
Protein Binding
Repressor Proteins antagonists & inhibitors
Repressor Proteins genetics
Signal Transduction
Arteries enzymology
Atherosclerosis enzymology
Histone Deacetylases metabolism
I-kappa B Kinase metabolism
Plaque, Atherosclerotic
Repressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 127
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 32546048
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.120.316743