Abstract 455: Inhibition of Histone Deacetylase 6 Activity Provides Protection Against Atherogenesis: a Role for HDAC6 NEDDylation
| Autor: | Anil Bhatta, Yohei Nomura, Max C. Rossberg, Lew Romer, Deepesh Pandey, Dan E. Berkowitz |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 38 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.38.suppl_1.455 |
| Popis: | Rationale: Histone Deacetylase 6 (HDAC6) regulates Cystathionine Gamma Lyase (CSEγ)- hydrogen sulfide producing enzyme known to play a critical role in endothelial function. However, a role for HDAC6 in atherogenesis is unknown. Objective: To determine whether pharmacological inhibition of HDAC6 inhibition by tubacin would attenuate atherogenesis and to elucidate specific molecular mechanism(s) that regulate endothelial HDAC6 activity. Methods and Results: We evaluated whether administration of tubacin attenuated or reversed the endothelial dysfunction and atherosclerosis induced in mice by a single i.p injection of PCSK9 AAV followed by a high fat diet (HFD) for 12 weeks. Tubacin significantly blunted PCSK9-induced increases in pulse wave velocity (index of vascular stiffness and overall vascular health) that are also seen in atherogenic mice. Furthermore, tubacin protected vessels from defective vasorelaxation, as evaluated by acetycholine-mediated relaxation using wire myograph. Plaque burden defined by Oil Red O staining was also found to be significantly less in mice that received tubacin than in those that received PCSK9 alone. Inhibition of the NEDD8 -activating enzyme 1 (NAE1) by MLN4924 significantly increased HDAC6 activity in Human Aortic Endothelial Cells (HAEC). Interestingly, levels of HDAC6 remain unchanged. This finding is consistent with the etiology of the change in function being the post-translational modification of HDAC6 by NEDD8, and not due to its overall abundance. HAEC exposed to the atherogenic stimulus OxLDL exhibited enhanced HDAC6 activity which was attenuated in a dose-response manner by pre-treatment with MLN4924. Conclusion: HDAC6 inhibition by tubacin and/or MLN4924 represents a novel pharmacological intervention for atherogenesis. |
| Databáze: | OpenAIRE |
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