Melatonin upregulates DNA-PKcs to suppress apoptosis of human umbilical vein endothelial cells via inhibiting miR-101 un
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Melatonin upregulates DNA-PKcs to suppress apoptosis of human umbilical vein endothelial cells via inhibiting miR-101 under H2O2induced oxidative stress Hao Gu1 · Jian Li2 · Rongrong Zhang1 Received: 17 May 2020 / Accepted: 16 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Melatonin has been implicated in inhibiting oxidative stress-induced apoptosis of endothelial cells. However, the underlying mechanism remains poorly understood. In this study, we examined the effect of melatonin on apoptosis of human umbilical vein endothelial cells (HUVECs) induced by H2O2 and explored the underlying mechanisms. Our results demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) upregulation contributed to the protective role of melatonin in HUVECs under oxidative stress with H 2O2. Further study showed that melatonin treatment led to a decreased level of miRNA-101, which could be responsible for DNA-PKcs upregulation and DNA-PKcs-mediated apoptosis inhibition in HUVECs under oxidative stress with H2O2. Our results also showed that melatonin increased the activity of PI3K/AKT and DNA-PKcs knockdown in melatonin-treated HUVECs that lead to inactivation of PI3K/AKT signaling under oxidative stress with H2O2. Furthermore, blockade of PI3K/AKT signal with LY294002 significantly reduced melatonin-induced apoptosis inhibition in H 2O2-treated HUVECs. Taken together, our findings identify a miR-101/DNA-PKcs/PI3K/AKT signaling pathway in melatonin-induced endothelial cell apoptosis inhibition under oxidative stress with H2O2. Keywords Melatonin · DNA-PKcs · miRNA-101 · Endothelial cells · Oxidative stress Abbreviations DNA-PKcs DNA-dependent protein kinase catalytic subunit HUVECs Human umbilical vein endothelial cells PIKK Phosphatidylinositol-3 kinase-like protein kinase ROS Reactive oxygen species Hao Gu and·Jian Li contributed equally to the manuscript * Rongrong Zhang [email protected] Hao Gu [email protected] Jian Li [email protected] 1
Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, No.1 the Yellow River West Road, Huaiyin District, Huai’an, Jiangsu 223300, People’s Republic of China
Department of Anesthesiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China
2
Introduction Endothelial cell apoptosis plays a primary role in the pathogenesis of angiogenic diseases, such as atherosclerosis, heart failure, and hypertension [1, 2]. Oxidative stress has been demonstrated to be a key pathogenic factor for endothelial cell apoptosis [3]. Therefore, inhibiting oxidative stressinduced endothelial cell apoptosis will be beneficial for treatment of angiogenic-related diseases. Melatonin is a natural endogenous hormone secreted from the pineal gland and shows significant therapeutic effects on angiogenic diseases due to its efficacy and lack of toxicity [4, 5]. Previous studies have demonstrated that melatonin has v
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