Elastin-derived peptides potentiate atherosclerosis through the immune Neu1–PI3Kγ pathway

Gayral, Stéphanie; Garnotel, Roselyne; Castaing-Berthou, Audrey; Blaise, Sébastien; Fougerat, Anne; Berge, Elodie; Montheil, Aurélie; Malet, Nicole; Wymann, Matthias P.; Maurice, Pascal; Debelle, Laurent; Martiny, Laurent; Martinez, Laurent O.; Pshezhetsky, Alexey V.; Duca, Laurent; Laffargue, Muriel

doi:10.1093/cvr/cvt336

Cited by 91 publications

(97 citation statements)

References 44 publications

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“…As a consequence, EDP, which concentration increases in blood circulation with age [6], are thought to be involved in several aging-related pathologies such as atherosclerosis [18] and cancer [15,16,19–21]. …”

Section: Introductionmentioning

confidence: 99%

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production

et al. 2015

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Degradation of elastin leads to the production of elastin-derived peptides (EDP), which exhibit several biological effects, such as cell proliferation or protease secretion. Binding of EDP on the elastin receptor complex (ERC) triggers lactosylceramide (LacCer) production and ERK1/2 activation following ERC Neu-1 subunit activation. The ability for ERC to transduce signals is lost during aging, but the mechanism involved is still unknown. In this study, we characterized an in vitro model of aging by subculturing human dermal fibroblasts. This model was used to understand the loss of EDP biological activities during aging. Our results show that ERC uncoupling does not rely on Neu-1 or PPCA mRNA or protein level changes. Furthermore, we observe that the membrane targeting of these subunits is not affected with aging. However, we evidence that Neu-1 activity and LacCer production are altered. Basal Neu-1 catalytic activity is strongly increased in aged cells. Consequently, EDP fail to promote Neu-1 catalytic activity and LacCer production in these cells. In conclusion, we propose, for the first time, an explanation for ERC uncoupling based on the age-related alterations of Neu-1 activity and LacCer production that may explain the loss of EDP-mediated effects occurring during aging.

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Section: Introductionmentioning

confidence: 99%

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production

et al. 2015

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“…These 3 subunits form a functional receptor in human platelets that is able to trigger an increase in sialidase activity on binding to EDP. In contrast to PPCA, the catalytic activity of Neu-1 has been shown to be essential for ERC-mediated effects both in vitro 19,32 and in vivo 13,14 by catalyzing the local conversion of GM 3 ganglioside into lactosylceramide. 19,32 Expression of Neu-1 and PPCA has been already reported in platelets.…”

Section: Discussionmentioning

confidence: 97%

“…On binding to an elastin-derived bioactive GxxPG peptide, such as VGVAPG, the ERC is able to decrease washed platelet aggregation and related signaling and to prolong arteriole occlusion and tail-bleeding time. Because the signaling pathways mediated by the ERC have been shown to transduce signals through the catalytic activity of its Neu-1 subunit, 13,14,36 this study opens new avenues in the complexity of the platelet signaling pathways involved during thrombosis and hemostasis and offers the exciting possibility of a potential fine-tuning of platelet receptor sialylation and activation by the ERC. …”

Section: Discussionmentioning

confidence: 99%

“…This peptide was used at a 4-fold higher concentration than kE (400 μg/mL) because it has been demonstrated that a 4-fold higher concentration is necessary to achieve the equivalent physiological stimulation levels of bioactive elastin peptides released after elastin degradation. 13,14,16 As negative control, a scrambled VVGPGA peptide was used. 17,18 As shown in Figure 2A and 2C, VGVAPG significantly decreased the area covered by platelets from 30 seconds of perfusion.…”

Section: Edp and Vgvapg Reduce Thrombus Formation In Vitro Under Flowmentioning

confidence: 99%

“…For instance, a proatherogenic role of EDP has been recently described in ApoE −/− and LDLR −/− mice. 13 In addition, chronic accumulation of EDP has been shown to promote hyperglycemia and insulin resistance in mice.…”

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confidence: 99%

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Elastin-Derived Peptides Are New Regulators of Thrombosis

Kawecki

Hézard

Bocquet

et al. 2014

ATVB

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Objective-Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. Approach and Results-We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappaelastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. Conclusions-These

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The Role of Elastin Degradation in Vascular Calcification: Possibilities to Repair Elastin and Reverse Calcification

Zohora

Nosoudi

Karamched

et al. 2020

Contemporary Cardiology

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Elastin-derived peptides potentiate atherosclerosis through the immune Neu1–PI3Kγ pathway

Abstract: Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in vivo.

Cited by 91 publications

References 44 publications

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production

Elastin-Derived Peptides Are New Regulators of Thrombosis

The Role of Elastin Degradation in Vascular Calcification: Possibilities to Repair Elastin and Reverse Calcification

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