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

Abstract

Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of HS. However, the molecular mechanisms that control CSEγ 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 CSEγ. Reduced CSEγ 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 CSEγ overexpression or the HS donor NaHS. CSEγ 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 CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ 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 CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and HS 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.

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

“…The anti-atherosclerotic mechanisms of H 2 S have been gradually described, including anti-inflammatory response, anti-oxidative action, endothelial function preservation, inhibition of foam cell formation and regulation of ion channels (Altaany et al, 2014;Mani et al, 2014;Xu et al, 2014;Wang et al, 2017;Barton and Meyer, 2019). Reduced CSE expressions at both mRNA and protein levels are detected in ox-LDL-treated endothelial cells and in aortas from apolipoprotein E knockout (ApoE -/-) mice (Leucker et al, 2017). In this study, the authors demonstrated that increased histone deacetylase 6 (HDAC6) downregulated CSE and H 2 S production via posttranslational modifications, thus leading to endothelial cell dysfunction and the development of atherosclerosis (Leucker et al, 2017).…”

“…Reduced CSE expressions at both mRNA and protein levels are detected in ox-LDL-treated endothelial cells and in aortas from apolipoprotein E knockout (ApoE -/-) mice (Leucker et al, 2017). In this study, the authors demonstrated that increased histone deacetylase 6 (HDAC6) downregulated CSE and H 2 S production via posttranslational modifications, thus leading to endothelial cell dysfunction and the development of atherosclerosis (Leucker et al, 2017). In cultured vascular endothelial cells, the expressions of miR-455-3p, endothelial nitric oxide synthase (eNOS) protein and NO production are augmented by H 2 S. Besides, H 2 S levels and miR-455-3p expressions are also increased in human atherosclerosis plaque, suggesting that the miR-455-3p/eNOS/NO axis is required to H 2 S to circumvent the development of atherosclerosis (Li et al, 2017).…”

Diabetic keto acidosis as a deceiving presentation to simultaneous aortic and tricuspid infective endocarditis

“…These findings highlight the dual effect of H 2 S to enhance the activating phosphorylation and reduce the inhibiting phosphorylation state of eNOS. In addition to enhancing the activity of eNOS via phosphorylation, H 2 S can directly stabilize the dimeric state of eNOS to enhance NO production as examined by Altaany et al [3]. In their studies, NaHS increased eNOS dimer/eNOS monomer ratio, Figure 2.…”

“…Within the vascular wall, several pathways produce H 2 S. A recent study by Leskova and co-workers in cultured HUVECS observed that these cells take up exogenous thiosulfate for later release as free H 2 S while numerous other studies report H 2 S production in the vascular wall by cystathionine gamma-lyase (CSE) [1][2][3][4][5][6][7], cystathionine betasynthase (CBS) [8][9][10] and 3-mercaptopyruvate sulfurtransfurase (3-MST) [11,12]. Thus, the synthesis of this gasotransmitter is not completely defined and remains an area of active investigation as discussed below.…”

Honokiol ameliorates angiotensin II‐induced hypertension and endothelial dysfunction by inhibiting HDAC6‐mediated cystathionine γ‐lyase degradation

“…17 In similar contexts, HDAC6 has been proposed as a therapeutic target for treatment of cardiovascular diseases. [15][16][17][18][19] We also recently reported that tubastatin A, an HDAC6-specific inhibitor, could increase CSE acetylation and enhance its protein levels and H 2 S production, thereby helping to attenuate the vasoconstriction and hypertension induced by AngII. 20 Moreover, HDAC6, a member of the class IIb HDAC family, exhibits distinct characters compared to other HDAC family members in that it has unique specificity for protein deacetylation of non-histone substrates such as α-tubulin, cortactin and heat-shock protein 90.…”