Zufeng Ding1, Shijie Liu2, Xianwei Wang3, Yao Dai3, Magomed Khaidakov3, Xiaoyan Deng4, Yubo Fan4, David Xiang3, Jawahar L Mehta5. 1. Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, PR China School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, PR China. 2. Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, PR China mehtajl@uams.edu sliu2@uams.edu. 3. Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 4. Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, PR China. 5. Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA mehtajl@uams.edu sliu2@uams.edu.
Abstract
AIMS: Lectin-like ox-LDL scavenger receptor-1 (LOX-1) and mitochondrial DNA (mtDNA) damage play a key role in a variety of cardiovascular diseases, including atherosclerosis, hypertension, and inflammation. We posited that damaged mtDNA could trigger autophagy and NLRP3 inflammasome activation, and LOX-1 may play a critical role in this process. METHODS AND RESULTS: In order to examine this hypothesis, cultured human THP-1 macrophages exposed to lipopolysaccharide (LPS) were applied to study the link between LOX-1, mtDNA damage, autophagy, and NLRP3 inflammasome expression. Our data showed that LPS markedly induced LOX-1 expression, reactive oxygen species (ROS) generation, autophagy, mtDNA damage, and NLRP3 inflammasome. LOX-1 inhibition with a binding antibody or siRNA inhibited ROS generation, autophagy and mtDNA damage, and a decreased expression of NLRP3 inflammasome. To study the LOX-1-NLRP3 inflammasome signalling, we performed studies using ROS inhibitors and an autophagy inducer, and found that both decreased the expression of NLRP3. On the other hand, autophagy inhibitor enhanced the expression of NLRP3 inflammasome. Knockdown of DNase II inhibited autophagy and NLRP3 inflammasome, providing further support for our hypothesis. Finally, we confirmed the relationship between LOX-1, ROS, mtDNA damage, autophagy, and NLRP3 inflammasome activation in primary macrophages. CONCLUSIONS: This study based on THP-1 macrophages and primary macrophages indicates that LOX-1-mediated autophagy and mtDNA damage play an essential role in NLRP3 inflammasome activation in inflammatory disease states. Published by Oxford University Press on behalf of the European Society of Cardiology 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
AIMS: Lectin-like ox-LDL scavenger receptor-1 (LOX-1) and mitochondrial DNA (mtDNA) damage play a key role in a variety of cardiovascular diseases, including atherosclerosis, hypertension, and inflammation. We posited that damaged mtDNA could trigger autophagy and NLRP3 inflammasome activation, and LOX-1 may play a critical role in this process. METHODS AND RESULTS: In order to examine this hypothesis, cultured humanTHP-1 macrophages exposed to lipopolysaccharide (LPS) were applied to study the link between LOX-1, mtDNA damage, autophagy, and NLRP3 inflammasome expression. Our data showed that LPS markedly induced LOX-1 expression, reactive oxygen species (ROS) generation, autophagy, mtDNA damage, and NLRP3 inflammasome. LOX-1 inhibition with a binding antibody or siRNA inhibited ROS generation, autophagy and mtDNA damage, and a decreased expression of NLRP3 inflammasome. To study the LOX-1-NLRP3 inflammasome signalling, we performed studies using ROS inhibitors and an autophagy inducer, and found that both decreased the expression of NLRP3. On the other hand, autophagy inhibitor enhanced the expression of NLRP3 inflammasome. Knockdown of DNase II inhibited autophagy and NLRP3 inflammasome, providing further support for our hypothesis. Finally, we confirmed the relationship between LOX-1, ROS, mtDNA damage, autophagy, and NLRP3 inflammasome activation in primary macrophages. CONCLUSIONS: This study based on THP-1 macrophages and primary macrophages indicates that LOX-1-mediated autophagy and mtDNA damage play an essential role in NLRP3 inflammasome activation in inflammatory disease states. Published by Oxford University Press on behalf of the European Society of Cardiology 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Authors: Philip Wenzel; Hanke Mollnau; Matthias Oelze; Eberhard Schulz; Jennifer M Dias Wickramanayake; Johanna Müller; Swenja Schuhmacher; Marcus Hortmann; Stephan Baldus; Tommaso Gori; Ralf P Brandes; Thomas Münzel; Andreas Daiber Journal: Antioxid Redox Signal Date: 2008-08 Impact factor: 8.401
Authors: Sabine Heumüller; Sven Wind; Eduardo Barbosa-Sicard; Harald H H W Schmidt; Rudi Busse; Katrin Schröder; Ralf P Brandes Journal: Hypertension Date: 2007-12-17 Impact factor: 10.190
Authors: Der-Yuan Chen; Tatsuya Sawamura; Richard A F Dixon; José Luis Sánchez-Quesada; Chu-Huang Chen Journal: J Clin Med Date: 2021-05-06 Impact factor: 4.241
Authors: Juan M Suárez-Rivero; Carmen J Pastor-Maldonado; Suleva Povea-Cabello; Mónica Álvarez-Córdoba; Irene Villalón-García; Marta Talaverón-Rey; Alejandra Suárez-Carrillo; Manuel Munuera-Cabeza; José A Sánchez-Alcázar Journal: Biomedicines Date: 2021-03-05