title: PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2.
abstract: The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome has been linked to sterile inflammation, which is involved in ischemic injury in myocardial cells. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein with many biological activities, such as anti-inflammatory, antioxidant and anti-angiogenic properties. However, it is not known whether and how PEDF acts to regulate the activation of the NLRP3 inflammasome in cardiomyocytes. In the present study, we used the neonatal cardiomyocytes models of ischemia-like conditions to evaluate the mitochondrial fission and the activation of the NLRP3 inflammasome. We also determined the mechanism by which PEDF inhibits hypoxia-induced activation of the NLRP3 inflammasome. We found that PEDF decreased the activation of the NLRP3 inflammasome in neonatal cardiomyocytes through pigment epithelial-derived factor receptor/calcium-independent phospholipase A2 (PEDFR/iPLA2). Meanwhile, PEDF reduced Drp1-induced mitochondrial fission and mitochondrial fission-induced mitochondrial DNA (mtDNA), as well as mitochondrial reactive oxygen species (mtROS) release into cytosol through PEDFR/iPLA2. We also found that PEDF inhibited mitochondrial fission-induced NLRP3 inflammasome activation. Furthermore, previous research has found that endogenous cytosolic mtDNA and mtROS can serve as activators of NLRP3 inflammasome activity. Therefore, we hypothesized that PEDF can protect against hypoxia-induced activation of the NLRP3 inflammasome by inhibiting mitochondrial fission though PEDFR/iPLA2.
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. zzzgqh@163.com.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. wzxy1984@163.com.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, China. guanqiuhua2008@163.com.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Guan
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. viovan@163.com.
authors.forename: Fan
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. 18761437629@163.com.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Facility Center for Morphology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China. gavinliu@xzmc.edu.cn.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. zhanghao@xzmc.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Research Facility Center for Morphology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China. dhy@xzmc.edu.cn.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China. zhang_zhongming@xzmc.edu.cn.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D063154:Mitochondrial Dynamics / Q000187:drug effects; D008954:Models, Biological; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D015843:Serpins / Q000494:pharmacology*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D004272:DNA, Mitochondrial; D005136:Eye Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009414:Nerve Growth Factors; D054467:Phospholipases A2; D017382:Reactive Oxygen Species; D018013:Receptors, Neuropeptide; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C573346:Nlrp3 protein, rat; C400531:pigment epithelium-derived factor receptor
keywords: dynamin-related peptide 1 (Drp1); mitochondrial fission; nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome; pigment epithelial-derived factor receptor (PEDFR); pigment epithelium-derived factor (PEDF)