Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang, Xu; Xu, Suowen; Liu, Peng; Koroleva, Marina; Zhang, Shuya; Si, Shuyi; Jin, Zheng Gen

doi:10.1161/jaha.117.007134

Cited by 51 publications

(32 citation statements)

References 52 publications

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“…KLF2 is known to induce vasoprotective effects in endothelial cells, including anti-inflammation, antithrombosis, anti-oxidative stress, and anti-proliferation. Modulating the expression of KLF2 is considered a promising treatment strategy against atherosclerosis and other cardiovascular diseases [42]. Here, we show that aloperine remarkably rescues KLF2 expression from the reduction induced by ox-LDL.…”

Section: Discussionmentioning

confidence: 62%

The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs

Zhao

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Atherosclerosis is a potentially life-threatening cardiovascular disease characterized by chronic endothelial inflammation and the formation of atherosclerotic lesions. Circulating ox-LDL is known to induce atherosclerosis by triggering oxidative stress, the expression of inflammatory mediators and adhesion molecules, as well as downregulating the atheroprotective transcriptional factor KLF2. Aloperine is an alkaloid compound isolated from the plant Sophora alopecuroides. Here, we employed various experimental methods to determine the effects of aloperine on ox-LDL-induced markers of atherosclerosis. DHE staining revealed that aloperine may restore the oxidant/antioxidant balance in HUVECs by reducing the level of ROS and rescuing the reduction in NOQ-1 and GCLC induced by ox-LDL. Aloperine treatment reduced ox-LDL-induced expression of IL-6, MCP-1, VCAM-1, and E-selectin and rescued the reduction in KLF2. Aloperine also downregulated ox-LDL-induced expression of the LOX-1. We also demonstrate that aloperine improved cell viability and inhibited the adhesion of U937 monocytes to HUVECs. Finally, we demonstrate that the effects of aloperine are mediated through the rescue of KLF2 expression via suppression of the phosphorylation of p53 protein. Together, our results implicate the potential of aloperine as a safe and effective antiatherosclerosis treatment.

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Section: Discussionmentioning

confidence: 62%

The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs

Zhao

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Mouse endothelial cells were isolated from adult C57BL/6J mouse lungs using collagenase I digestion (3 mg/mL in serum-free DMEM) at 37 °C in an incubator for 45 min, followed by CD31- and ICAM2-dynabeads-based double positive selection 45 , 46 . The isolated mouse lung endothelial cells were authenticated by endothelial marker VE-cadherin staining.…”

Section: Methodsmentioning

confidence: 99%

Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects

Xu¹,

Yang²,

Yin³

et al. 2018

Theranostics

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Rationale: Atherosclerosis is a chronic inflammatory and epigenetic disease that is influenced by different patterns of blood flow. However, the epigenetic mechanism whereby atheroprotective flow controls endothelial gene programming remains elusive. Here, we investigated the possibility that flow alters endothelial gene expression through epigenetic mechanisms.Methods: En face staining and western blot were used to detect protein expression. Real-time PCR was used to determine relative gene expression. RNA-sequencing of human umbilical vein endothelial cells treated with siRNA of enhancer of zeste homolog 2 (EZH2) or laminar flow was used for transcriptional profiling.Results: We found that trimethylation of histone 3 lysine 27 (H3K27me3), a repressive epigenetic mark that orchestrates gene repression, was reduced in laminar flow areas of mouse aorta and flow-treated human endothelial cells. The decrease of H3K27me3 paralleled a reduction in the epigenetic “writer”-EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2). Moreover, laminar flow decreased expression of EZH2 via mechanosensitive miR101. Genome-wide transcriptome profiling studies in endothelial cells treated with EZH2 siRNA and flow revealed the upregulation of novel mechanosensitive gene IGFBP5 (insulin-like growth factor-binding protein 5), which is epigenetically silenced by H3K27me3. Functionally, inhibition of H3K27me3 by EZH2 siRNA or GSK126 (a specific EZH2 inhibitor) reduced H3K27me3 levels and monocyte adhesion to endothelial cells. Adenoviral overexpression of IGFBP5 also recapitulated the anti-inflammatory effects of H3K27me3 inhibition. More importantly, we observed EZH2 upregulation, and IGFBP5 downregulation, in advanced atherosclerotic plaques from human patients.Conclusion: Taken together, our findings reveal that atheroprotective flow reduces H3K27me3 as a chromatin-based mechanism to augment the expression of genes that confer an anti-inflammatory response in the endothelium. Our study exemplifies flow-dependent epigenetic regulation of endothelial gene expression, and also suggests that targeting the EZH2/H3K27me3/IGFBP5 pathway may offer novel therapeutics for inflammatory disorders such as atherosclerosis.

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“…Resveratrol also activates KLF4 via the MEK5/ MEF2-dependent signaling pathway in endothelial cells [22]. SAHA (also known as vorinostat), a pan-inhibitor of histone deacetylases, has been identified as a pharmacological activator of KLF2 by luciferase reporter assay-based high throughput drug screening [70]. SAHA exhibits potent anti-inflammatory effects and reduces monocyte adhesion to activated endothelial cells.…”

Section: Activators Of Klf2 and Klf4mentioning

confidence: 99%

Targeting Mechanosensitive Transcription Factors in Atherosclerosis

Niu

Yang³

et al. 2019

Trends in Pharmacological Sciences

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128

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Atherosclerosis is the devastating underlying cause of cardiovascular disease and it preferentially develops at arterial regions exposed to disturbed flow (DF), while much less at regions of unidirectional laminar flow (UF). Recent studies have demonstrated that DF and UF differentially regulate important aspects of endothelial function, such as vascular inflammation, oxidative stress, vascular tone, cell proliferation, senescence, mitochondrial function, and glucose metabolism. DF and UF regulate vascular pathophysiology via differential regulation of mechanosensitive transcription factors (MSTFs) (KLF2, KLF4, NRF2, YAP/TAZ/TEAD, HIF-1α, NF-κB, AP-1 and others). Emerging studies show that MSTFs represent promising therapeutic targets for the prevention and treatment of atherosclerosis. Here, we present a comprehensive overview of the role of MSTFs in atherosclerosis and highlight future directions for developing novel therapeutic agents by targeting MSTFs.

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Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Cited by 51 publications

References 52 publications

The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs

The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs

Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects

Targeting Mechanosensitive Transcription Factors in Atherosclerosis

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