Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation

Xu, Yiming; Wang, Yong; Yan, Siyuan; Yang, Qiuhua; Zhou, Yuwen; Zeng, Xiangwu; Liu, Zhiping; An, Xiaofei; Toque, Haroldo A.; Dong, Zheng; Jiang, Xuejun; Fulton, David; Weintraub, Neal L.; Li, Qinkai; Bagi, Zsolt; Hong, Mei; Boison, Detlev; Wu, Chaodong; Huo, Yuqing

doi:10.1038/s41467-017-00986-7

Cited by 81 publications

(53 citation statements)

References 46 publications

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“…ADK-L is reported to affect epigenetic remodeling [19,20] and is thought to preferentially function as a regulator of methyltransferase action through clearance of adenosine [17,21]. On the other hand, ADK-S regulates extracellular adenosine concentration to activate various adenosine receptor subtypes and affects angiogenesis [22], inflammation [20], and immune suppression [23]. These functions of ADK isoforms strongly support a differential role for ADK-L versus ADK-S in cancer.…”

Section: Introductionmentioning

confidence: 96%

“…This differential expression suggests a distinctive role for ADK-L (versus ADK-S) on proliferation and differentiation -two major nuclear activities that are tightly linked to cancer pathology [18]. ADK-L is reported to affect epigenetic remodeling [19,20] and is thought to preferentially function as a regulator of methyltransferase action through clearance of adenosine [17,21]. On the other hand, ADK-S regulates extracellular adenosine concentration to activate various adenosine receptor subtypes and affects angiogenesis [22], inflammation [20], and immune suppression [23].…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of adenosine kinase isoforms in breast cancer

et al. 2019

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Dysregulated adenosine signaling pathway has been evidenced in the pathogenesis of breast cancer. However, the role of adenosine kinase (ADK) in tumorigenesis remains unclear while it crucially regulates the removal and availability of adenosine. ADK has two isoforms that localize to discrete subcellular spaces: i.e., nuclear, long-isoform (ADK-L) and cytosolic, short-isoform (ADK-S). We hypothesized that these two ADK isoforms would be differentially expressed in breast cancer and may contribute to divergent cellular actions in cancer. In this study, we examined the expression profiles of ADK isoforms in breast cancer tissues from 46 patient and followed up with an in vitro investigation by knocking down the expression of ADK-L or ADK-S using CRISPR gene editing to evaluate the role of ADK isoform in cancer progression and metastasis of cultured triple-negative breast cancer cell line MDA-MB-231. We demonstrated that (i) ADK-L expression level was significantly increased in breast cancer tissues versus paired normal tissues adjacent to tumor, whereas the ADK-S expression levels were not significantly different between cancerous and normal tissues; (ii) CRISPR/Cas9-mediated downregulation of ADK isoforms, led to suppressed cellular proliferation, division, and migration of cultured breast cancer cells; (iii) ADK-L knockdown significantly upregulated gene expression of matrix metalloproteinase (ADAM23, 9.93-fold; MMP9, 24.58-fold) and downregulated expression of cyclin D2 (CCND2,-30.76-fold), adhesive glycoprotein THBS1 (-8.28fold), and cystatin E/M (CST6,-16.32-fold). Our findings suggest a potential role of ADK-L in mitogenesis, tumorigenesis, and tumor-associated tissue remodeling and invasion; and the manipulation of ADK-L holds promise as a therapeutic strategy for aggressive breast cancer.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Dysregulation of adenosine kinase isoforms in breast cancer

et al. 2019

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“…Ischemic reperfusion injury, characterized as myocardial damage and unstoppable cell death . Numerous studies have identified various pathological factors involved in the pathological process, including mitochondrial dysfunction, inflammatory response, endoplasmic reticulum stress, and oxidative stress . Despite extensive efforts having been put into the research of myocardial infarction and ischemic reperfusion injury, there still existed little effective treatment and intervention target …”

Section: Introductionmentioning

confidence: 99%

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

Tian

et al. 2019

IUBMB Life

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Acute myocardial infarction is one of the most threatening disease in the world. In previous studies, numerous dysregulated lncRNAs exposed to ischemic reperfusion injury have been identified. In this differential lncRNAs, Gm2691 attracted our attention due to its high fold change. The aim of the study was to investigate the function and mechanism of lncRNA Gm2691 in ischemic reperfusion injury. AnaeroPack anaerobic system treated neonatal rat ventricular cardiomyocytes were used to analyze the function of lncRNA Gm2691 in vitro. Tunel, Caspase3, and inflammation markers were detected to evaluate apoptosis and inflammatory response. Rat acute myocardial infarction was performed to elucidate the function of lncRNA Gm2691 in vivo. The results showed that LncRNA Gm2691 improved the cardiac function and attenuated the inflammatory response in vivo. We also found that lncRNA Gm2691 reduced the apoptosis and improved cell survival rates in anaeroPack anaerobic system treated neonatal rat ventricular cardiomyocytes. Western blot analysis revealed that lncRNA Gm2691 decreased Akt and ERK1/2 activities, suggesting that lncRNA Gm2691 may functioned through Akt signaling pathway. We verified the function and mechanism of lncRNA Gm2691 and provide evidence that lncRNA Gm2691 may play important role in ischemic reperfusion injury, and understanding the precise role of Gm2691 will undoubtedly shed new light on the clinical treatment.

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“…Specifically, endothelial cells play an essential role in maintaining the blood brain barrier, while endothelial dysfunction contributes to vascular disease and stroke (Roquer et al, 2009). Inflammation and apoptosis can induce endothelial damage after stroke (Suzuki and Urano, 2011;Xu et al, 2017). Our results showed that NLRP3 in the endothelial cells after SAH could be mitigated by hydrogen inhalation.…”

Section: Discussionmentioning

confidence: 71%

Hydrogen Inhalation Attenuates Oxidative Stress Related Endothelial Cells Injury After Subarachnoid Hemorrhage in Rats

et al. 2020

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Background: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with poor clinical outcome. Nucleotide binding and oligomerization domainlike receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves a key role in inflammatory response, which may lead to endothelial cell injury and blood-brain barrier (BBB) disruption. Hydrogen (H 2) is considered a neuroprotective antioxidant. This study was set out to explore whether hydrogen inhalation protects against SAH induced endothelial cell injury, BBB disruption, microthrombosis and vasospasm in rats. Methods: One hundred eighty-two male SD rats were used for the study. SAH was induced by endovascular perforation. H2 at a concentration of 3.3% was inhaled beginning at 0.5 h after SAH for duration of 30, 60 or 120 min, followed by single administration or once daily administration for 3 days. The temporal expression of NLRP3 and ASC in the brain was determined, with the effect of hydrogen inhalation evaluated. In addition, brain water content, oxidative stress markers, inflammasome, apoptotic markers, microthrombosis, and vasospasm were evaluated at 24 or 72 h after SAH. Results: The expression of NLRP3 and ASC were upregulated after SAH associated with elevated expression of MDA, 8-OHdG, 4-HNE, HO-1, TLR4/NF-κB, inflammatory and apoptotic makers. Hydrogen inhalation reduced the expression of these inflammatory and apoptotic makers in the vessels, brain edema, microthrombi formation, and vasospasm in rats with SAH relative to control. Hydrogen inhalation also improved short-term and long-term neurological recovery after SAH. Conclusion: Hydrogen inhalation can ameliorate oxidative stress related endothelial cells injury in the brain and improve neurobehavioral outcomes in rats following SAH. Mechanistically, the above beneficial effects might be related to, at least in part, the inhibition of activation of ROS/NLRP3 axis.

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Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation

Cited by 81 publications

References 46 publications

Dysregulation of adenosine kinase isoforms in breast cancer

Dysregulation of adenosine kinase isoforms in breast cancer

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

Hydrogen Inhalation Attenuates Oxidative Stress Related Endothelial Cells Injury After Subarachnoid Hemorrhage in Rats

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