Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation.

Szczegóły
Abstrakt

Tytuł:: Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation.
Autorzy:: Kimura Y; From the Department of Internal Medicine, Faculty of Medicine (Y.K., T.Y., A.O., D.T., H.K.), Teikyo University, Tokyo, Japan.
Yanagida T; From the Department of Internal Medicine, Faculty of Medicine (Y.K., T.Y., A.O., D.T., H.K.), Teikyo University, Tokyo, Japan.
Onda A; From the Department of Internal Medicine, Faculty of Medicine (Y.K., T.Y., A.O., D.T., H.K.), Teikyo University, Tokyo, Japan.
Tsukui D; From the Department of Internal Medicine, Faculty of Medicine (Y.K., T.Y., A.O., D.T., H.K.), Teikyo University, Tokyo, Japan.
Hosoyamada M; Department of Human Physiology and Pathology, Faculty of Pharma-Sciences (M.H.), Teikyo University, Tokyo, Japan.
Kono H; From the Department of Internal Medicine, Faculty of Medicine (Y.K., T.Y., A.O., D.T., H.K.), Teikyo University, Tokyo, Japan.
Źródło:: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2020 Mar; Vol. 40 (3), pp. 570-582. Date of Electronic Publication: 2020 Jan 30.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
MeSH Terms:: AMP-Activated Protein Kinases/*metabolism
Atherosclerosis/*enzymology
Inflammation/*enzymology
Leukocytes, Mononuclear/*enzymology
Uric Acid/*blood
Adult ; Animals ; Atherosclerosis/blood ; Atherosclerosis/pathology ; Atherosclerosis/prevention & control ; Benzbromarone/administration & dosage ; Biomarkers/blood ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Female ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Inflammasomes/genetics ; Inflammasomes/metabolism ; Inflammation/blood ; Inflammation/pathology ; Inflammation/prevention & control ; Inflammation Mediators/blood ; Interleukin-18/blood ; Interleukin-1beta/blood ; Interleukin-1beta/genetics ; Leukocytes, Mononuclear/drug effects ; Male ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Nuclear Factor 45 Protein/blood ; Plaque, Atherosclerotic ; Reactive Oxygen Species/metabolism ; Receptors, LDL/deficiency ; Receptors, LDL/genetics ; Urate Oxidase/genetics ; Urate Oxidase/metabolism ; Uricosuric Agents/administration & dosage ; Xanthine Oxidase/antagonists & inhibitors ; Xanthine Oxidase/metabolism ; Young Adult
Contributed Indexing:: Keywords: humans; inflammation; interleukin-1; mice; uric acid
Substance Nomenclature:: 0 (Biomarkers)
0 (Enzyme Inhibitors)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (IL1B protein, human)
0 (ILF2 protein, human)
0 (Inflammasomes)
0 (Inflammation Mediators)
0 (Interleukin-18)
0 (Interleukin-1beta)
0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (NLRP3 protein, human)
0 (Nuclear Factor 45 Protein)
0 (Reactive Oxygen Species)
0 (Receptors, LDL)
0 (Uricosuric Agents)
268B43MJ25 (Uric Acid)
4POG0RL69O (Benzbromarone)
EC 1.17.3.2 (Xanthine Oxidase)
EC 1.7.3.3 (Urate Oxidase)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
Entry Date(s):: Date Created: 20200131 Date Completed: 20200714 Latest Revision: 20200714
Update Code:: 20240105
DOI:: 10.1161/ATVBAHA.119.313224
PMID:: 31996020
: Czasopismo naukowe

Objective: Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine.
Conclusions: The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

Informacja