Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis

Hurtado, Begoña; Abasolo, Nerea; Muñoz, Xavier; García, Nadia; Benavente, Yolanda; Rubio, Francisco; Frutos, Pablo García de; Krupiński, Jerzy; Sala, Núria

doi:10.1160/th09-11-0787

Cited by 34 publications

(40 citation statements)

References 33 publications

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“…58 These mechanisms can possibly explain part of the recent findings that SNP mutations in TAM receptor genes are correlated with the formation of atherosclerotic plaques. 59,60 Protein S is upregulated by interleukin-4 (IL-4) in primary T cells. 61 Natural killer T cells require Mer to induce the transcription of IL-4 and interferon-g (IFN-g).…”

Section: Tam Receptorsmentioning

confidence: 99%

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Meer

Poll

Veer

2014

Blood

283

228

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TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K–dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S+/−, Gas6−/−, TAM−/−, and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

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Section: Tam Receptorsmentioning

confidence: 99%

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Meer

Poll

Veer

2014

Blood

283

228

View full text Add to dashboard Cite

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“…Numerous studies have identified that Gas6/ Axl pathway plays a pivotal role in vascular biology and diseases such as vascular calcification, vascular remodeling, and atherosclerosis (Hurtado et al 2011;Korshunov et al 2006;Lutgens et al 2008;Son et al 2010). Moreover, the polymorphism of gas6 gene has been associated with stroke and acute coronary syndrome in humans (Hurtado et al 2010;Munoz et al 2007). Clinical research shows that the plasma concentration of Gas6 decreases with age and is associated with the testosterone level (Hung et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl-and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin IIinduced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin IIinduced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, AxlFc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/ FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

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“…Factor XIII Val34Leu polymorphism was detected using fluorescent PCR and hybridization probes [47]. Similar methodology was used for the genotyping of Gas6 rs8191974 (c.834+7G.A) polymorphism and for the MerTK rs86016 (g.2920G.A) polymorphism, as described earlier [46]. Complement C3 rs2230199 (p.Arg102Gly) polymorphism was tested using a PCR-RFLP method.…”

Section: Molecular Genetic Methodsmentioning

confidence: 99%

“…The candidate, most likely a tag SNP, that has been shown to be associated with AMD, rs10033900 in the complement factor I (CFI) gene was tested using TaqMan SNP Genotyping assay. TaqMan assays were also used for the detection of the MerTK I1b rs17835605 (g.4916C.T), MerTK I1c rs10496440 (g.8809A.C) and MerTK I4 rs7573344 (g.60127A.G), as described earlier [46]. Over 98% of controls and 96% of patients were genotyped in each test.…”

Section: Molecular Genetic Methodsmentioning

confidence: 99%

“…Haplotype (defined as a group of closely linked polymorphic alleles in a chromosomal region) tagging SNPs were selected according to the following parameters: MAF.0.05 in Caucasians, r2.0.8 between each pair of tagged and tagging SNPs in pairwise tagging and haplotypes coverage down to 5% of their frequency in the HapMap CEU population for each analysed gene. The 4 tagSNPs selected belong to a haplotype block and were sufficient to cover the whole gene [46].…”

Section: Introductionmentioning

confidence: 99%

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The effect of a Gas6 c.834+7G>a polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients

Losonczy

Balogh

Vajas

et al. 2012

Acta Ophthalmologica

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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G.A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26-0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30-393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98-12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G.A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD.

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Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis

Cited by 34 publications

References 33 publications

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

The effect of a Gas6 c.834+7G>a polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients

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