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Kaiso protects human umbilical vein endothelial cells against apoptosis by differentially regulating the expression of B-cell CLL/lymphoma 2 family members.

ABSTRACT: Endothelial cell injury can promote the development of various cardiovascular diseases, thus, fully understanding the mechanisms underlying the maintenance of vascular endothelial cell homoeostasis may help prevent and treat cardiovascular disease. Kaiso, a zinc finger and BTB domain containing transcription factor, is key to embryonic development and cancer, but how Kaiso interacts with vascular endothelium is not fully understood. We report that Kaiso has an anti-apoptotic function in human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMEC-1s). Overexpression of Kaiso significantly increased cell viability and inhibited hydrogen peroxide-induced apoptosis. Furthermore, Kaiso increased expression of B-cell CLL/lymphoma 2 (BCL2) and reduced expression of BCL2-associated X protein (BAX) and BCL2-interacting killer (BIK) by differentially regulating gene promoter activity. Methylated DNA and specific Kaiso binding site (KBS) contributed to gene regulatory activity of Kaiso. In addition, p120ctn functioned cooperatively in Kaiso-mediated transcriptional regulation.

SUBMITTER: Xue X

PROVIDER: S-EPMC5540925 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Kaiso protects human umbilical vein endothelial cells against apoptosis by differentially regulating the expression of B-cell CLL/lymphoma 2 family members.

Xue Xiaodong X Zhang Jian J Lan Huai H Xu Yinli Y Wang Huishan H

Scientific reports 20170802 1

Endothelial cell injury can promote the development of various cardiovascular diseases, thus, fully understanding the mechanisms underlying the maintenance of vascular endothelial cell homoeostasis may help prevent and treat cardiovascular disease. Kaiso, a zinc finger and BTB domain containing transcription factor, is key to embryonic development and cancer, but how Kaiso interacts with vascular endothelium is not fully understood. We report that Kaiso has an anti-apoptotic function in human um ...[more]

PMID: 28769046

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Project description:Background/aimsOxidative stress-induced damage in endothelial cells is a crucial initiator of atherosclerosis (AS), which is highly related to excessive reactive oxygen species (ROS) and mitochondrial dynamics. Resveratrol (RSV) exerts beneficial effects against endothelial oxidative injury, while the underlying mechanisms have not been fully elucidated. Thus, we aimed to explore the role of mitochondria dynamics during the anti-oxidative activities of RSV in palmitic acid (PA)-stimulated human umbilical vein endothelial cells (HUVECs) and to verify whether tyrosyl transfer- RNA synthetase (TyrRS) and poly (ADP-ribose) polymerase 1 (PARP1) are targeted during this process.MethodsHUVECs were exposed to 200 μM of PA for 16 h before treated with 10 μM of RSV for 8 h. Cell viability was detected using Cell counting kit-8 (CCK-8) assay. The intracellular ROS level and mitochondria membrane potential (MMP) were measured using microplate reader and flow cytometry. The malondialdehyde and superoxide dismutase were measured using the microplate reader. The mitochondrial morphology and fusion process was observed under transmission electron microscopy and confocal microscopy. TyrRS and PARP1 were knocked down with the specific small interference RNAs (siRNA), and the protein expressions of TyrRS, PARP1, and mitochondrial fusion proteins (MFN1, MFN2, and OPA1) were measured by western blot.ResultsRSV treatment suppressed the PA-induced injuries in HUVECs, including the damage to cell viability, oxidative stress, and loss of MMP. Additionally, RSV improved the protein levels of MFN1, MFN2, and OPA1 as well as inhibited the PA-induced fragmentation of mitochondria. However, the effects of RSV on oxidative stress and mitochondrial fusion were abolished by the pretreatment of siRNAs of TyrRS and PARP1, indicating that these effects of RSV were dependent on the TyrRS-PARP1 pathway.ConclusionsRSV attenuated endothelial oxidative injury by regulating mitochondrial fusion via TyrRS-PARP1 signaling pathway.

Project description:The increasing burden of diabetes in low and middle‑income countries is attributable to both genetic and epigenetic factors. Environmental‑ and lifestyle‑associated changes are also considered to be important contributors to this disease. The resultant co‑morbidities arising from micro‑and macrovascular changes in diabetes are difficult to manage and are an economic burden. However, very little is known about the molecular mechanisms that drive this phenotype. The present study aimed to investigate the role of sirtuin 1 (SIRT1)‑ and transcription box‑3 (TBX‑3)‑mediated regulation of endothelial dysfunction, given the significance of SIRT1 in glucose metabolism and the role of TBX‑3 in the maintenance of cellular proliferation, senescence and apoptosis. Following the recruitment of adult patients with and without diabetes, both SIRT1 and TBX‑3 expression was confirmed to be present in the sera of the patients with diabetes and the patients without diabetes; however, both SIRT1 and TBX‑3 expression levels were higher in the sera of the patients with diabetes. Human umbilical vein endothelial cells (HUVECs) were further used for in vitro studies. Using TBX‑3 and SIRT1 knockdown models, the cellular responses to proliferation, migration, invasion and tube formation were investigated using an MTS, cell cycle analysis, wound healing, Transwell and tube formation assay, respectively. Western blotting was also used to determine the downstream signaling pathways involved. The genetic knockdown of TBX‑3 in hyperglycemic conditions significantly decreased the cellular proliferation, migration, invasion and angiogenesis of HUVECs. It was subsequently identified that TBX‑3 mediated its effects through the activation of AKT and vascular endothelial growth factor (VEGF) signaling. However, the genetic knockdown of SIRT1 in the presence of TBX‑3 overexpression and glucose failed to activate the AKT and VEGF signaling pathways. In conclusion, the results of the present study suggested that SIRT1 may positively regulate TBX‑3 in endothelial cells, therefore, SIRT1 and/or TBX‑3 may serve as potential novel biomarkers for disease progression.

Dataset Information

Kaiso protects human umbilical vein endothelial cells against apoptosis by differentially regulating the expression of B-cell CLL/lymphoma 2 family members.

Publications

Kaiso protects human umbilical vein endothelial cells against apoptosis by differentially regulating the expression of B-cell CLL/lymphoma 2 family members.

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