The identification and function of a Netrin-1 mutation in a pedigree with premature atherosclerosis.

Atherosclerosis
Caroline S BruikmanJanine M van Gils

Abstract

Neuroimmune guidance cues have been shown to play a role in atherosclerosis, but their exact role in human pathophysiology is largely unknown. In the current study, we investigated the role of a c.1769G > T variant in Netrin-1 in (premature) atherosclerosis. To determine the effect of the genetic variation, purified Netrin-1, either wild type (wtNetrin-1) or the patient observed variation (mutNetrin-1), was used for migration, adhesion, endothelial barrier function and bindings assays. Expression of adhesion molecules and transcription proteins was analyzed by RT-PCR, Western blot or ELISA. To further delineate how mutNetrin-1 mediates its effect on cell migration, lenti-viral knockdown of UNC5B or DCC was used. Bindings assays revealed a decreased binding capacity of mutNetrin-1 to the receptors UNC5B, DCC and β3-integrin and an increased binding capacity to neogenin, heparin and heparan sulfate compared to wtNetrin-1. Exposure of endothelial cells to mutNetrin-1 resulted in enhanced monocyte adhesion and expression of IL-6, CCL2 and ICAM-1 compared to wtNetrin-1. In addition, mutNetrin-1 lacks the inhibitory effect on the NF-κB pathway that is observed for wtNetrin-1. Moreover, the presence of mutNetrin-1 diminished migration...Continue Reading

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Citations

Apr 4, 2021·International Journal of Molecular Sciences·Michal Kowara, Agnieszka Cudnoch-Jedrzejewska
May 8, 2021·Atherosclerosis·Christoph J BinderArnold von Eckardstein
Jul 23, 2021·Circulation Research·Martin SchlegelKathryn J Moore

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