The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase

Chen, Jihui; Zhang, Jian; Shaik, Noor F.; Yi, Bing; Wei, Xin; Yang, Xiaofeng; Naik, Ulhas P.; Summer, Ross; Yan, Guijun; Xu, Xinyun; Sun, Jianxin

doi:10.1074/jbc.ra119.011317

Cited by 23 publications

(28 citation statements)

References 60 publications

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“…An increasing interest in the potential therapeutic effects of arginine supplementation, especially in cardiovascular disorders, has recently emerged. An impaired NO synthesis is considered a main feature of a dysfunctional endothelium [ 107 , 134 , 135 , 136 ]; however, several studies suggest that arginine supplementation in healthy subjects does not lead to a significant increase in NO production [ 11 , 137 , 138 , 139 , 140 ]. For instance, the daily administration of arginine for 1 week did not affect the serum concentration of two established indicators of NO production, namely NO 2 − and NO 3 − , in twelve healthy subjects [ 138 ].…”

Section: Arginine and No Production In Physiological Conditions: Tmentioning

confidence: 99%

Arginine and Endothelial Function

et al. 2020

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Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus.

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Section: Arginine and No Production In Physiological Conditions: Tmentioning

confidence: 99%

Arginine and Endothelial Function

et al. 2020

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“…Otherwise, FK228 a kind of selective HDAC1/2 inhibitor could help restrain TOPK through the AKT pathway to attenuate the oxidative stress in the early stage of ischemic stroke. Besides that, in 2019, tubacin selectively inhibits HDAC6 activity which had been identified in transient occlusion of the middle cerebral artery by ameliorating endothelial dysfunction [ 58 ].…”

Section: Hdacs In Cerebral Ischemiamentioning

confidence: 99%

Updating a Strategy for Histone Deacetylases and Its Inhibitors in the Potential Treatment of Cerebral Ischemic Stroke

Wang

Chen

et al. 2020

Disease Markers

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Background. Cerebral ischemic stroke is one of the severe diseases with a pathological condition that leads to nerve cell dysfunction with seldom available therapy options. Currently, there are few proven effective treatments available for improving cerebral ischemic stroke outcome. However, recently, there is increasing evidence that inhibition of histone deacetylase (HDAC) activity exerts a strong protective effect in in vivo and vitro models of ischemic stroke. Review Summary. HDAC is a posttranslational modification that is negatively regulated by histone acetyltransferase (HATS) and histone deacetylase. Based on function and DNA sequence similarity, histone deacetylases (HDACs) are organized into four different subclasses (I-IV). Modifications of histones play a crucial role in cerebral ischemic affair development after translation by modulating disrupted acetylation homeostasis. HDAC inhibitors (HDACi) mainly exert neuroprotective effects by enhancing histone and nonhistone acetylation levels and enhancing gene expression and protein modification functions. This article reviews HDAC and its inhibitors, hoping to find meaningful therapeutic targets. Conclusions. HDAC may be a new biological target for cerebral ischemic stroke. Future drug development targeting HDAC may make it a potentially effective anticerebral ischemic stroke drug.

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“…Hypermethylation of the DDAH2 promoter was associated with DDAH2 downregulation in human umbilical vein endothelial cells and the rat corpora cavernosa, whereas the inhibition of methylation using 5'-aza-2'-deoxycytidine enhanced DDAH2 expression in undifferentiated cells of trophoblast cell lineage (10)(11)(12). Acetylation is an important epigenetic modification that has been reported to regulate NOS expression by various mechanisms (13,14). To the best of our knowledge, mechanistically, only Tomikawa et al (12) previously reported that histone acetylation regulated the expression of DDAH2 in trophoblast stem cells and was involved in the regulation of cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

Regulation of dimethylarginine dimethylaminohydrolase 2 expression by NF‑κB acetylation

Sun

2020

Exp Ther Med

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Nitric oxide (NO) serves a crucial role in the kidney and is synthesized by NO synthase (NOS). Asymmetrical dimethylarginine is an endogenous inhibitor of NOS that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To investigate the role of acetylation in DDAH2 expression, 293 cells were treated with trichostatin A (TSA), a deacetylase inhibitor and the mRNA and protein levels were assessed using quantitative PCR and western blotting respectively. Its promoter activity was detected using a luciferase assay. The effect of TSA on NF-κB acetylation was tested after immunoprecipitation. The binding of NF-κB to the DDAH2 promoter was analyzed using an electrophoretic mobility shift assay and chromatin immunoprecipitation. TSA upregulated DDAH2 expression and transcriptional activity of the DDAH2 promoter through a NF-κB responsive element, which is located at the-1582 to-1573 position of the DDAH2 promoter. Furthermore, TSA treatment promoted NF-κB acetylation, resulting in enhanced NF-κB binding affinity to its binding site both in vitro and in vivo. Taken together, the present study demonstrated that NF-κB acetylation upregulated DDAH2 expression by enhancing the binding ability of NF-κB to the DDAH2 promoter, resulting in increased promoter activity. The results provided a possible mechanism underlying the regulation of NO production in renal cells and a potential target for treating certain NO-associated renal disorders.

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The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase

Cited by 23 publications

References 60 publications

Arginine and Endothelial Function

Arginine and Endothelial Function

Updating a Strategy for Histone Deacetylases and Its Inhibitors in the Potential Treatment of Cerebral Ischemic Stroke

Regulation of dimethylarginine dimethylaminohydrolase 2 expression by NF‑κB acetylation

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