Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation to Limit Intimal Hyperplasia

Panchatcharam, Manikandan; Miriyala, Sumitra; Salous, Abdelghaffar K.; Wheeler, Jessica; Dong, Anping; Müeller, Paul; Sunkara, Manjula; Escalante‐Alcalde, Diana; Morris, Andrew J.; Smyth, Susan S.

doi:10.1161/atvbaha.112.300527

Cited by 46 publications

(53 citation statements)

References 42 publications

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“…However, available data indicate that the risk-associated PPAP2B allele predicts lower mRNA expression in blood cells. Inactivation of the PPAP2B gene in vascular smooth muscle cells leads to exaggerated neointima formation in response to arterial injury in vivo and enhanced migration, proliferation, and differentiation responses of cultured vascular smooth muscle cells to LPA in vitro ( 15 ). These observations support the idea that PPAP2B is normally protective against at least the vascular smooth muscle cell mediated component of experimental atherothrombotic disease.…”

supporting

confidence: 68%

Lysophosphatidic acid and cardiovascular disease: seeing is believing

Morris

Smyth

2013

Journal of Lipid Research

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supporting

confidence: 68%

Lysophosphatidic acid and cardiovascular disease: seeing is believing

Morris

Smyth

2013

Journal of Lipid Research

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“…It has been reported that LPA promotes hepatocyte secretion of apoBcontaining proteins ( 12 ) and it is possible that some of the changes noted here may be due to changes in plasma LPA levels acting on the liver. Regardless of the mechanism(s) the data presented here further add to the growing body of evidence suggesting that LPA plays a major role in lipid metabolism, infl ammation, and atherosclerosis ( 7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 59%

“…In vivo in LDLR Ϫ / Ϫ mice, it was shown that application of a collar to the carotid artery resulted in a time-dependent increase in artery LPA levels ( 18 ). Also in vivo, mice with selective inactivation of lipid phosphate phosphatase 3 displayed an exaggerated neointimal response to injury ( 19 ). The gene for lipid phosphate phosphatase 3 was identifi ed as a susceptibility locus for coronary artery disease ( 20 ).…”

mentioning

confidence: 99%

Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid

Navab

Hough

Buga

et al. 2013

Journal of Lipid Research

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. Transgenic 6F tomatoes act on the small intestine to prevent systemic infl ammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid. J. Lipid Res. 2013. 54: 3403-3418. Supplementary key words 6F peptide • apolipoprotein A-I mimetic peptides • atherosclerosis • lysophosphatidic acid • genetically engineered tomato plantsMimetics of apolipoprotein A-I (apoA-I) containing only 18 amino acids showed promise in animal models of disease ( 1, 2 ), and improved HDL function in humans when given orally at high doses despite achieving low plasma peptide levels ( 3 ). However, when high plasma levels were achieved with low doses of peptide given intravenously or by subcutaneous (SQ) injection, no improvement in HDL function was seen ( 4 ). Studies in mice surprisingly suggested that the major site of action for these peptides is in the Abstract We recently reported that levels of unsaturated lysophosphatidic acid (LPA) in the small intestine significantly correlated with the extent of aortic atherosclerosis in LDL receptor-null (LDLR ؊ / ؊ ) mice fed a Western diet (WD). Here we demonstrate that WD increases unsaturated (but not saturated) LPA levels in the small intestine of LDLR ؊ / ؊ mice and causes changes in small intestine gene expression. Confi rmation of microarray analysis by quantitative RT-PCR showed that adding transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F) to WD prevented many WD-mediated small intestine changes in gene expression. If instead of feeding WD, unsaturated LPA was added to chow and fed to the mice: i ) levels of LPA in the small intestine were similar to those induced by feeding WD; ii ) gene expression changes in the small intestine mimicked WD-mediated changes; and iii ) changes in plasma serum amyloid A, total cholesterol, triglycerides, HDLcholesterol levels, and the fast-performance liquid chromatography lipoprotein profi le mimicked WD-mediated changes. Adding Tg6F (but not control tomatoes) to LPA-supplemented chow prevented the LPA-induced changes. We conclude that: i ) WD-mediated systemic infl ammation and dyslipidemia may be in part due to WD-induced increases in small intestine LPA levels; and ii ) Tg6F reduces WD-mediated systemic infl ammation and dyslipidemia by preventing WDinduced increases in LPA levels in the small intestine. -Navab, M., G. Hough, G. M. Buga, F. Su, A. C. Wagner, D. Meriwether, A. Chattopadhyay, F. Gao, V. Grijalva, J. S. Danciger, B. J. Van Lenten, E. Org, A. J. Lusis, C. Pan, G. M. the Laubisch, Castera, and M. K. Grey Abbreviations: CXCL1, chemokine (CXC motif) ligand 1; EV, empty vector tomatoes (transgenic tomatoes constructed with the vector pBI121 containing the GUS gene; 6F, This work was supported in part bycontaining all L -amino acids; FPLC, fast-performance liquid chromatography; LDLR Ϫ / Ϫ , LDL receptor-null; LPA, lysophosphatidic acid; PA, phosphatidic acid; PPAR, peroxisome proliferatoractivated receptor; RT-qPCR, quantitative RT-PCR ; SAA, serum amyloid A; SQ, subcutaneous; Tg6F, t...

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“…In ECs, PPAP2B localizes to adherens junctions and regulates ␤ -catenin signaling, thereby affecting cell migration ( 34 ). In SMCs, it regulates lysophospholipid signaling responses and affects SMC phenotypic plasticity ( 35 ). Our results indicate that PPAP2B may be involved in susceptibility to atherosclerosis via its dual function in vascular wall cells.…”

Section: Discussionmentioning

confidence: 79%

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Erbilgin

Civelek²,

Romanoski³

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org provided insight into the many different genetic factors that contribute to the disease ( 3-7 ). Using data acquired from thousands of patients and healthy controls, these studies have collectively identifi ed 35 genetic loci associated with CAD ( 8, 9 ). Although 10 of the recently identifi ed CAD risk loci work through known risk factors, such as lipids and blood pressure, this is not the case for the majority of loci ( 3 ), implying that key pathways leading to coronary atherosclerosis are yet to be discovered. Given their fi rm association with disease risk, novel CAD loci provide a solid foundation to unravel disease networks.As GWAS results do not provide functional information on the loci identifi ed, additional studies are needed to determine the candidate genes and their role in disease. The immediate challenges associated with the validation of GWAS candidate genes include identifying the likely cell types in which the risk variants and genes function, determining which of the multiple candidate genes represented by each CAD locus contribute to disease, and defi ning the functions of poorly annotated candidate genes. Expression analyses of candidate genes under defi ned conditions in model organisms and their associations with risk variants in human samples provide a powerful way to address these issues and predict the causal candidate genes.It is likely that at least some of the novel genes (that is, those not affecting known risk factors, such as plasma lipids or blood pressure) are perturbing vessel wall or infl ammatory cell functions. Endothelial cells (EC) play a critical role in the initiation and progression of atherosclerosis. Abstract Recent genome-wide association studies (GWAS)have identifi ed 35 loci that signifi cantly associate with coronary artery disease (CAD) susceptibility. The majority of the genes represented in these loci have not previously been studied in the context of atherosclerosis. To characterize the roles of these candidate genes in the vessel wall, we determined their expression levels in endothelial, smooth muscle, and macrophage cells isolated from healthy, prelesioned, and lesioned mouse aortas. We also performed expression quantitative locus (eQTL) mapping of these genes in human endothelial cells under control and proatherogenic conditions. Of the 57 genes studied, 31 were differentially expressed in one or more cell types in disease state in mice, and the expression levels of 8 were signifi cantly associated with the CAD SNPs in human cells, 7 of which were also differentially expressed in mice. By integrating human and mouse results, we predict that PPAP2B , GALNT4 , MAPKAPK5 , TCTN1 , SRR , SNF8 , and ICAM1 play a causal role in the susceptibility to atherosclerosis through a role in the vasculature. Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilib...

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Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation to Limit Intimal Hyperplasia

Cited by 46 publications

References 42 publications

Lysophosphatidic acid and cardiovascular disease: seeing is believing

Lysophosphatidic acid and cardiovascular disease: seeing is believing

Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

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