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

Abstract

Endothelial cystathionine gamma-lyase (CSEgamma) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSEgamma 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 CSEgamma. Reduced CSEgamma 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 mug/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEgamma overexpression or the H2S donor NaHS. CSEgamma 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 CSEgamma expression and blocked OxLDL-mediated reductions in endothelial CSEgamma expression and CSEgamma promoter activity, indicating that HDAC6 is a specific regulator of CSEgamma 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, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEgamma expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis.NEW & NOTEWORTHY Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine gamma-lyase (CSEgamma) expression and H2S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.