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Int. J. Mol. Sci. 2016, 17(12), 2064; doi:10.3390/ijms17122064

PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2

1
Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China
2
Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, China
3
Research Facility Center for Morphology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: H. W. M. Niessen
Received: 21 September 2016 / Revised: 26 November 2016 / Accepted: 2 December 2016 / Published: 12 December 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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. View Full-Text
Keywords: pigment epithelium-derived factor (PEDF); pigment epithelial-derived factor receptor (PEDFR); nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome; mitochondrial fission; dynamin-related peptide 1 (Drp1) pigment epithelium-derived factor (PEDF); pigment epithelial-derived factor receptor (PEDFR); nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome; mitochondrial fission; dynamin-related peptide 1 (Drp1)
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MDPI and ACS Style

Zhou, Z.; Wang, Z.; Guan, Q.; Qiu, F.; Li, Y.; Liu, Z.; Zhang, H.; Dong, H.; Zhang, Z. PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2. Int. J. Mol. Sci. 2016, 17, 2064.

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