Abstract TMP26: Binding of KLF4 and HDAC2 to The Promoter Region of SM22alpha Mediates Phenotypic Modulation In vitro and In vivo: Implications in Cerebral Aneurysm Formation

• DOI: 10.1161/str.44.suppl_1.atmp26
• Publication Date: 2021-07-03T12:02:14Z
• Authors: Robert M Starke; Muhammad S Ali; Stavropoula I Tjo...; Pascal M Jabbour; L. Fernando Gonzalez; Robert H Starke; Walter J Koch; Aaron S Dumont
• Keywords: Chromatin immunoprecipitation; KLF4

Cerebral Vascular Smooth Muscle Cell (VSMC) phenotypic modulation appears to play an important role in cerebral aneurysm formation and progression, yet the molecular mechanisms involved remain unknown. We investigated of inflammatory cytokine, Tumor Necrosis Factor-alpha (TNF-α) cigarette smoke directly mediating VSMC. hypothesize that this may, part, occur through binding transcription factor, KLF4, promoter region SM22alpha, thereby downregulating VSMC differentiation contractile genes. This may be critical pathogenesis formation. Methods: Cultured from rat Circle Willis were treated with increasing doses TNF-α (10ng/ml & 50ng/ml) extract (CSE; 10ug/ml 40ug/ml) 2 24hrs. transfected siRNA specific KLF4. In vivo experiments included application pluronic gel (containing CSE) carotid artery adventitia. Expression SM22alpha KLF4 was measured qPCR. Chromatin Immunoprecipitation (ChIP) performed both vitro after treatment (TNF-α incubation anti-KLF4, anti-HDAC2, anti-H4Ac anti-H3K9Ac. Results: Both CSE independently suppress increase expression vivo. siKLF4 inhibits effects on SM22alpha. ChIP assays demonstrate binds further recruits HDAC2 region. complex leads histone modifications leading decreased acetylation H4 H3K9, resulting Conclusion: is a key mediator induced Phenotypic has been implicated humans. dependent regulation underlying mechanism target for future therapies.