Lipid phosphate phosphatase 3 maintains NO-Mediated flow-mediated dilation in human adipose resistance arterioles.

KEY POINTS: LPP3 expression is reduced in patients with coronary artery disease (CAD). Loss of LPP3 in CAD is associated with an increase in the LPP3 inhibitor, miR-92a. Inhibition of LPP3 in the microvascular of healthy patients mimics the CAD FMD phenotype. Inhibition of miR-92a restores NO-mediated FMD in the microvasculature of CAD patients. ABSTRACT: Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow-mediated dilation (FMD) from nitric oxide (NO) to mitochondrial-derived hydrogen peroxide (H2 O2 ) 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 H2 O2 (% maximal dilation: Control 78.1±11.4% vs Peg-Cat 30.0±11.2%; p<0.0001). miR-92a is elevated in CAD arterioles (Fold change: 1.9±0.0.1 p = 0.04), while inhibition of miR-92a restored NO-mediated FMD (CAD) and enhancing miR-92a expression (non-CAD) elicited H2 O2 -mediated dilation (p<0.0001). Our data suggests LPP3 is crucial in the disease-associated switch in the mediator of FMD. Abstract figure legend Maintenance of Lipid Phosphate Phosphatase 3 (LPP3) Maintains Microvascular Function in Health and Disease. A. In healthy microvasculature, LPP3 helps tranduce the production of shear-induced nitric oxide (NO) formation to induce smooth muscle relaxation (flow-mediated dilation). B. In microvascular disease, such as coronary artery disease, miR-92a inhibits expression of LPP3, and increases production of mitochondrial-derived reactive oxygen species (ROS) to cause a switch in the mechanism of microvascular flow-mediated dialtion from NO to H2 O2 This article is protected by copyright. All rights reserved.