Targeted Disruption of JCAD (Junctional Protein Associated With Coronary Artery Disease)/KIAA1462, a Coronary Artery Disease–Associated Gene Product, Inhibits Angiogenic Processes In Vitro and In Vivo

Hara, Tetsuya; Monguchi, Tomoko; Iwamoto, Noriko; Akashi, Mitsuru; Mori, Kensaku; Oshita, Toshihiko; Okano, Mitsumasa; Toh, Ryuji; Irino, Yasuhiro; Shinohara, Masakazu; Yamashita, Yui; Shioi, Go; Furuse, Mikio; Ishida, Tatsuro; Hirata, Ken‐ichi

doi:10.1161/atvbaha.117.309721

Cited by 26 publications

(28 citation statements)

References 29 publications

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“…KIAA1462 has been previously reported in the same locus identified by GWAS for CHD 21 . This gene encodes a protein involved in cell–cell junctions in endothelial cells 22 , which was recently shown to be involved in pathologic angiogenic process in in vitro and in vivo experimental models 23 . These findings suggest that there may be important differences in vascular bed regulation at distinctive regions for atherosclerotic cardiovascular and stroke outcomes that may help to identify genes and specific targets for CHD or stroke prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Franceschini¹,

Giambartolomei²,

Vries³

et al. 2018

Nat Commun

141

119

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Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

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Section: Discussionmentioning

confidence: 99%

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Franceschini¹,

Giambartolomei²,

Vries³

et al. 2018

Nat Commun

141

119

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“…Indeed, the advantage of having a tumor line from the most used mouse strain, C57BL/6, makes it possible to have a lot of genetically modified models of this strain. Thus, EO771 cell tumor growth can be evaluated i) in KO mice for E2 (estradiol), 23 apolipoprotein E and aromatase, 42 IFN‐γ receptor, 48 natural killer lytic‐associated molecule (NKLAM), 33 MMP13, 49 calcium‐independent phospholipase A2 β, 50 IGFBP‐3, 21,51,52 DUSP1, 53 GDF2, 54 BMP10, 54 and mKIAA1462 55 but also ii) in transgenic models such as mice overexpressing IL‐15, 56 obese, 13,35 NKC KD (exhibiting silenced Ly49 expression in NK cells), 46 GFP‐LC3 (LC3 linked to GFP expressing mice), 57 mice transgenically modified to express the HER2 proto‐oncogene (ERBB2) 58 or FAT‐1 (gene leading to the endogenous formation of ω3‐Polyunsaturated fatty acid from ω6‐Polyunsaturated fatty acid) 44,59 …”

Section: Eo771 Mammary Tumor Mouse Modelsmentioning

confidence: 99%

“…Tumor development seems to be dependent on angiogenesis. A decrease in neovascularization is found in a mouse model using mKIAA1462 ‐/‐ mice resulting in a loss of “junctional protein associated with coronary artery disease,” and is associated with a decrease in tumor volume compared with the control group of EO771 tumor‐bearing mice 55 . Antiangiogenic agents targeting VEGF or its receptors have been tested in this model.…”

Section: Sensitivity To Different Therapiesmentioning

confidence: 99%

EO771, is it a well‐characterized cell line for mouse mammary cancer model? Limit and uncertainty

2020

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Among mouse mammary tumor models, syngeneic cell lines present an advantage for the study of immune response. However, few of these models are well characterized. The tumor line EO771 is derived from spontaneous breast cancer of C57BL/6 mice. These cells are widely used but are referenced under different names: EO771, EO 771, and E0771. The characteristics of the EO771 cells are well described but some data are contradictory. This cell line presents the great interest of developing an immunocompetent neoplastic model using an orthotopic implantation reflecting the mammary tumors encountered in breast cancer patients. This review presents the phenotype characteristics of EO771 and its sensitivity to nutrients and different therapies such as radiotherapy, chemotherapy, hormone therapy, and immunotherapy.

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“… 18 In our study, the reduced recovery of limb perfusion at later time points is most likely due to reduced angiogenesis. Loss of Jcad is associated with reduced tumour angiogenesis 5 and impaired VEGF signalling in endothelial cells, with reductions in VEGF mediated proliferation, migration, and tube formation. 3 , 5 …”

Section: Discussionmentioning

confidence: 99%

“… 4 A role for JCAD has been identified in pathological angiogenesis with decrease vascular formation in response to matrigel and decreased tumour growth. 5 We have recently identified JCAD as a negative regulator of Hippo signalling in endothelial cells, suggesting that JCAD may in part contribute to endothelial dysfunction by down-regulation of Hippo signalling, leading to increased YAP activity. 3 These observations support the results from previous proteomic studies which implicated JCAD as an interactor in the Hippo pathway, 6 , 7 and as a negative regulator of LATS2 kinase activity.…”

Section: Introductionmentioning

confidence: 99%

A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction

Douglas

Mehta

Zen

et al. 2019

Cardiovascular Research

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Aims Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis. Methods and results Vascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt. Conclusion The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway.

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Targeted Disruption of JCAD (Junctional Protein Associated With Coronary Artery Disease)/KIAA1462, a Coronary Artery Disease–Associated Gene Product, Inhibits Angiogenic Processes In Vitro and In Vivo

Abstract: These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis but serves a pivotal role in pathological angiogenic process after birth.

Cited by 26 publications

References 29 publications

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

EO771, is it a well‐characterized cell line for mouse mammary cancer model? Limit and uncertainty

A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction

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