Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation

Hoose, Patrick M Van; Yang, Liping; Kræmer, Maria; Ubele, Margo F.; Morris, Andrew J.; Smyth, Susan S.

doi:10.1038/s41598-022-08422-7

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…This is unlikely considering LPP3 has been detected in the endothelium of large vessels (Aldi et al., 2018; Wu et al., 2015), cultured endothelial cells from large human vessels (Touat‐Hamici et al., 2016; Wu et al., 2015), mouse endothelium (Panchatcharam et al., 2014) and microvascular endothelial cells (Chatterjee et al., 2016). LPP3 has also been detected in smooth muscle cells of animal and human large vessels (Panchatcharam et al., 2013; Van Hoose et al., 2022) but with limited data on microvasculature. It is possible that the protein levels in human arterioles are below the detection limit using the immunological methods and other, more sensitive methods need to be employed, such as mass spectrometry.…”

Section: Discussionmentioning

confidence: 99%

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

Chabowski

Hughes

Hockenberry

et al. 2023

The Journal of Physiology

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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 < 0.0001). miR‐92a is elevated in CAD arterioles (fold change: 1.9 ± 0.01 P = 0.04), while inhibition of miR‐92a restored NO‐mediated FMD (CAD), and enhancing miR‐92a expression (non‐CAD) elicited H2O2‐mediated dilatation (P < 0.0001). Our data suggests LPP3 is crucial in the disease‐associated switch in the mediator of FMD. Key points Lipid phosphate phosphatase 3 (LPP3) expression is reduced in heart tissue 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 microvasculature of healthy patients mimics the CAD flow‐mediated dilatation (FMD) phenotype. Inhibition of miR‐92a restores nitric oxide‐mediated FMD in the microvasculature of CAD patients.

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Section: Discussionmentioning

confidence: 99%

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

Chabowski

Hughes

Hockenberry

et al. 2023

The Journal of Physiology

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“…As noted above, LPA promoted atherosclerosis in mice [4], and mice deficient in LPA receptor 4 (LPA 4 ) were shown to be protected from atherosclerosis [5]. The work of Van Hoose et al [23 ▪▪ ] shows that SMC LPA protected against the formation of Ang II-induced abdominal aortic aneurysms in a mouse model of atherosclerosis, thus, demonstrating the complexity of the multiple roles that LPA can play in vascular diseases.…”

Section: Lysophosphatidic Acid Signaling Promotes Atherosclerosis But...mentioning

confidence: 90%

“…Infusion of angiotensin II into Ldlr -/- mice on a Western diet is an established model for producing abdominal aortic aneurysms [22]. Van Hoose et al [23 ▪▪ ] studied Ldlr -/- mice with Plpp3 deficiency that were induced to develop abdominal aortic aneurysms by feeding them a Western diet and infusing them with angiotensin II (Ang II). Ang II infusion increased the expression of Plpp3 in smooth muscle cells (SMCs) through nuclear factor kappa B signaling [23 ▪▪ ].…”

Section: Lysophosphatidic Acid Signaling Promotes Atherosclerosis But...mentioning

confidence: 99%

“…Van Hoose et al [23 ▪▪ ] studied Ldlr -/- mice with Plpp3 deficiency that were induced to develop abdominal aortic aneurysms by feeding them a Western diet and infusing them with angiotensin II (Ang II). Ang II infusion increased the expression of Plpp3 in smooth muscle cells (SMCs) through nuclear factor kappa B signaling [23 ▪▪ ]. Reduction of Plpp3 either globally in Plpp3 +/- mice or by SMC specific knockout protected the mice from aneurysm formation and transmural rupture.…”

Section: Lysophosphatidic Acid Signaling Promotes Atherosclerosis But...mentioning

confidence: 99%

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The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

Chattopadhyay

Reddy

Fogelman

2023

Current Opinion in Lipidology

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Purpose of review To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. Recent findings A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. Summary LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

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“…This mouse model mimics the hypercholesterolemic phenotype of LDLR deficient mice in exhibiting high plasma non-high-density lipoproteins concentrations and accelerated atherosclerosis formation when fed a Western diet [ 11 , 12 , 13 ]. Of note, injection of AAVs containing the mouse PCSK9 D377Y (AAV.mPCSK9 D377Y ) also augmented AngII-induced AAA formation in C57BL/6J mice, with comparable AAA severity to LDLR deficient mice with AngII infusion [ 14 , 15 , 16 , 17 ]. Thus, injection of AAVs containing a PCSK9 gain-of-function mutant saves the cost and time for generating mice to an LDLR deficient background.…”

Section: Introductionmentioning

confidence: 99%

Expression of a PCSK9 Gain-of-Function Mutation in C57BL/6J Mice to Facilitate Angiotensin II-Induced AAAs

2022

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Angiotensin II (AngII) infusion in mice has been used widely to investigate mechanisms of abdominal aortic aneurysms (AAAs). To achieve a high incidence of AngII-induced AAAs, mice should be hypercholesterolemic. Therefore, either low-density lipoprotein receptor (LDLR) or apolipoprotein E deficiency have been used as a hypercholesterolemic background. However, it is a time-consuming and expensive process to generate compound deficient strains that have either an LDLR or apolipoprotein E deficient background. Proprotein convertase subtilisin/kexin type 9 (PCSK9) facilitates the degradation of LDL receptors. Previous studies demonstrated profound increases of plasma cholesterol concentrations after a single intraperitoneal injection of adeno-associated viruses (AAV) expressing a gain-of-function mutation of mouse PCSK9 (AAV.mPCSK9D377Y) in C57BL/6J mice fed a Western diet. Of note, injection of AAV.mPCSK9D377Y augmented AngII-induced AAA formation in C57BL/6J mice that had comparable severity of AAAs to LDLR deficient mice. Thus, AAV.mPCSK9D377Y infection greatly expedites studies on a gene of interest using AngII-induced AAAs. This commentary provides a brief technical guide of this approach and discusses the pros and cons of its use in AAA research.

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Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation

Cited by 5 publications

References 49 publications

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

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

The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

Expression of a PCSK9 Gain-of-Function Mutation in C57BL/6J Mice to Facilitate Angiotensin II-Induced AAAs

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