Cystathionine {gamma}-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

Endothelial cystathionine -lyase (CSE) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSE gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSE. Reduced CSE mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE–/–) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSE overexpression or the H2S donor NaHS. CSE expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSE expression and blocked OxLDL-mediated reductions in endothelial CSE expression and CSE promoter activity, indicating that HDAC6 is a specific regulator of CSE expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE–/– mice were comparable to those in controls, wherea...

Source: AJP: Heart and Circulatory Physiology - April 1, 2017 Category: Cardiology Authors: Leucker, T. M., Nomura, Y., Kim, J. H., Bhatta, A., Wang, V., Wecker, A., Jandu, S., Santhanam, L., Berkowitz, D., Romer, L., Pandey, D. Tags: RESEARCH ARTICLE Source Type: research