Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts

Raymond Q. Migrino, Hannah A. Davies, Seth Truran, Nina Karamanova, Daniel A. Franco, Thomas G. Beach, Geidy E. Serrano, Danh Truong, Mehdi Nikkhah, Jillian Madine

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Aims: Medin is a common amyloidogenic protein in humans that accumulates in arteries with advanced age and has been implicated in vascular degeneration. Medin's effect on endothelial function remains unknown. The aims are to assess medin's effects on human arteriole endothelial function and identify potential mechanisms underlying medin-induced vascular injury.

Methods and results: Ex vivo human adipose and leptomeningeal arterioles were exposed (1 h) to medin (0.1, 1, or 5 µM) without or with FPS-ZM1 [100 µM, receptor for advanced glycation endproducts (RAGE)-specific inhibitor] and endothelium-dependent function (acetylcholine dilator response) and endothelium-independent function (dilator response to nitric oxide donor diethylenetriamine NONOate) were compared with baseline control. Human umbilical vein endothelial cells were exposed to medin without or with FPS-ZM1 and oxidative and nitrative stress, cell viability, and pro-inflammatory signaling measures were obtained. Medin caused impaired endothelial function (vs. baseline response: -45.2 ± 5.1 and -35.8 ± 7.9% in adipose and leptomeningeal arterioles, respectively, each P < 0.05). Dilator response to NONOate was not significantly changed. Medin decreased arteriole and endothelial cell nitric oxide production, increased superoxide production, reduced endothelial cell viability, proliferation, and migration. Medin increased gene and protein expression of interleukin-6 and interleukin-8 via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Medin-induced endothelial dysfunction and oxidative stress were reversed by antioxidant polyethylene glycol superoxide dismutase and by RAGE inhibitor FPS-ZM1.

Conclusions: Medin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury.

Original languageEnglish (US)
Pages (from-to)1389-1402
Number of pages14
JournalCardiovascular Research
Volume113
Issue number11
DOIs
StatePublished - Sep 1 2017

Keywords

  • Amyloid
  • Endothelial function
  • Inflammation
  • Medin
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Migrino, R. Q., Davies, H. A., Truran, S., Karamanova, N., Franco, D. A., Beach, T. G., Serrano, G. E., Truong, D., Nikkhah, M., & Madine, J. (2017). Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts. Cardiovascular Research, 113(11), 1389-1402. https://doi.org/10.1093/cvr/cvx135