Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes

Authors

Khamis Mustafa, Institute of Heart and Vessel Diseases, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Ying Han, Department of Cardiology, Jinqiu Hospital of Liaoning Province, Shenyang, China.
Dan He, Institute of Heart and Vessel Diseases, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Ying Wang, Institute of Heart and Vessel Diseases, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Nan Niu, Department of Cardiology, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Pedro A. Jose, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, District of Columbia, United States of America.
Yinong Jiang, Department of Cardiology, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
Jeffrey B. Kopp, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Hewang Lee, Institute of Heart and Vessel Diseases, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Peng Qu, Institute of Heart and Vessel Diseases, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

Document Type

Journal Article

Publication Date

1-1-2024

Journal

PloS one

Volume

19

Issue

2

DOI

10.1371/journal.pone.0295837

Abstract

Poly-(ADP-ribose) polymerases (PARPs) are a protein family that make ADP-ribose modifications on target genes and proteins. PARP family members contribute to the pathogenesis of chronic inflammatory diseases, including atherosclerosis, in which monocytes/macrophages play important roles. PARP inhibition is protective against atherosclerosis. However, the mechanisms by which PARP inhibition exerts this beneficial effect are not well understood. Here we show that in THP-1 monocytes, inhibition of PARP by olaparib attenuated oxidized low-density lipoprotein (oxLDL)-induced protein expressions of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing-3 (NLRP3) inflammasome components: NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. Consistent with this effect, olaparib decreased oxLDL-enhanced interleukin (IL)-1β and IL-18 protein expression. Olaparib also decreased the oxLDL-mediated increase in mitochondrial reactive oxygen species. Similar to the effects of the NLRP3 inhibitor, MCC950, olaparib attenuated oxLDL-induced adhesion of monocytes to cultured human umbilical vein endothelial cells and reduced foam cell formation. Furthermore, olaparib attenuated the oxLDL-mediated activation of nuclear factor (NF)-κB through the oxLDL-mediated increase in IκBα phosphorylation and assembly of NF-κB subunits, demonstrated by co-immunoprecipitation of IκBα with RelA/p50 and RelB/p52 subunits. Moreover, PARP inhibition decreased oxLDL-mediated protein expression of a NF-κB target gene, VCAM1, encoding vascular cell adhesion molecule-1. This finding indicates an important role for NF-κB activity in PARP-mediated activation of the NLRP3 inflammasome. Thus, PARP inhibition by olaparib attenuates NF-κB and NLRP3 inflammasome activities, lessening monocyte cell adhesion and macrophage foam cell formation. These inhibitory effects of olaparib on NLRP3 activity potentially protect against atherosclerosis.

APA Citation

Mustafa, Khamis; Han, Ying; He, Dan; Wang, Ying; Niu, Nan; Jose, Pedro A.; Jiang, Yinong; Kopp, Jeffrey B.; Lee, Hewang; and Qu, Peng, "Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes" (2024). GW Authored Works. Paper 4366.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4366

Department

Medicine