Lipid phosphate phosphatase 3 maintains NO‐mediated flow‐mediated dilatation in human adipose resistance arterioles

Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow‐mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial‐derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease...

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Bibliographic Details
Published in:The Journal of physiology 2023-02, Vol.601 (3), p.469-481
Main Authors: Chabowski, Dawid S., Hughes, William E., Hockenberry, Joseph C., LoGiudice, John, Beyer, Andreas M., Gutterman, David D.
Format: Article
Language:English
Subjects:
Animal models
Animals
Arterioles
Arterioles - metabolism
Arteriosclerosis
Cardiovascular disease
Cells, Cultured
Coronary artery disease
Coronary Artery Disease - genetics
Coronary vessels
Dilatation
flow‐mediated dilatation
Gene expression
Gene polymorphism
Heart diseases
Humans
Hydrogen peroxide
lipid phosphate phosphatase 3
Lipids
Lysophosphatidic acid
MicroRNAs - genetics
MicroRNAs - metabolism
Microvasculature
miR‐92a
Mitochondria
Nitric Oxide
Phenotypes
Phosphatase
Reactive oxygen species
Risk factors
Vasodilation - physiology
Vein & artery diseases
Ventricle
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Summary:Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow‐mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial‐derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease (CAD). The underlying mechanisms governing this shift are not completely defined. Lipid phosphate phosphatase 3 (LPP3) is a transmembrane protein that dephosphorylates lysophosphatidic acid, a bioactive lipid, causing a receptor‐mediated increase in reactive oxygen species. A single nucleotide loss‐of‐function polymorphism in the gene coding for LPP3 (rs17114036) is associated with elevated risk for CAD, independent of traditional risk factors. LPP3 is suppressed by miR‐92a, which is elevated in the circulation of patients with CAD. Repression of LPP3 increases vascular inflammation and atherosclerosis in animal models. We investigated the role of LPP3 and miR‐92a as a mechanism for microvascular dysfunction in CAD. We hypothesized that modulation of LPP3 is critically involved in the disease‐associated shift in mediator of FMD. LPP3 protein expression was reduced in left ventricle tissue from CAD relative to non‐CAD patients (P = 0.004), with mRNA expression unchanged (P = 0.96). Reducing LPP3 expression (non‐CAD) caused a shift from NO to H2O2 (% maximal dilatation: Control 78.1 ± 11.4% vs. Peg‐Cat 30.0 ± 11.2%; P 
ISSN:0022-3751
1469-7793
DOI:10.1113/JP283923