Role of histone deacetylase 9 in pro inflammatory responses in monocytes and macrophages

Yu, Lydia Luya (2022): Role of histone deacetylase 9 in pro inflammatory responses in monocytes and macrophages. Dissertation, LMU München: Faculty of Medicine

Abstract

Background: The histone deacetylase 9 (HDAC9) gene region on chromosome 7p21.1 has been identified as a major risk locus for large-vessel stroke, coronary and peripheral artery disease and atherosclerotic aortic calcification. The pro-atherogenic role of HDAC9 has been well established in experimental mouse models. However, the mechanisms linking HDAC9 to atherosclerosis remain poorly understood. Methods: Pro-inflammatory responses were studied in vivo using peritonitis models in Hdac9-/-Apoe-/- and control littermates and in vitro in primary mouse macrophages. The NF-κB signaling pathway was explored by immunoblotting. Furthermore, we investigated the effects of pharmacological class IIa HDAC inhibitor TMP195 on atherosclerosis in Apoe-/- mice by immunohistochemistry and examined effects on NF-κB signaling and on human monocyte activation by immunoblotting and ELISA. Results: We showed that Hdac9 deficiency results in attenuated inflammation. This was demonstrated by reduced leukocyte recruitment in vivo under acute inflammatory conditions and a reduction of pro-inflammatory and pro-atherogenic chemokines and cytokines in vivo and in vitro in primary as well as peritoneal macrophages. Mechanistically, HDAC9 enhanced p65 phosphorylation at serine residues 536 and 468 in primary macrophages. Treatment with the selective class IIa HDAC inhibitor TMP195 resulted in reduction of pro-inflammatory cytokine production by BMDMs from Apoe-/- mice, limited p65 phosphorylation and attenuated atherosclerotic plaque development in vivo. Moreover, TMP195 had limiting effects on cytokine production in monocytes from both healthy donors (n=5-6) and patients with established atherosclerosis (n=10-12). Conclusions: The results demonstrate a pro-inflammatory and pro-atherogenic role of HDAC9 in macrophages and monocytes and identify an activating effect of HDAC9 on NF-κB signaling. Importantly, selective pharmacological inhibition of these HDAC9-dependent mechanisms with the class IIa HDAC inhibitor TMP195 acts as a promising novel therapeutic approach to prevent vascular inflammation.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 10. November 2022
• 1. Referee: Dichgans, Martin
• Signature of the printed copy: 0700/UMD 20744