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Amyloidogenic Medin Induces Endothelial Dysfunction and Vascular Inflammation Through the Receptor for Advanced Glycation Endproducts
Author(s) -
Migrino Raymond Q.,
Davies Hannah,
Truran Seth,
Karamanova Nina,
Franco Daniel A.,
Serrano Geidy,
Beach Thomas,
Madine Jillian
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.19
Subject(s) - adipose tissue , endothelial dysfunction , endocrinology , dilator , medicine , arteriole , inflammation , nitric oxide , endothelium , chemistry , microcirculation
Aims Medin is a common amyloidogenic protein in humans, especially in older individuals. It has been implicated in the development of arterial degenerative changes associated with vascular aging. The mechanisms underlying medin‐induced vascular injury remain unknown. The aims are to assess medin's effects on human peripheral and central arteriole endothelial function, nitrative stress and vascular inflammation and identify potential mechanisms of injury. Methods and Results Ex‐vivo human adipose and leptomeningeal arterioles were exposed (1 hour) to medin (0.1, 1 or 5 μM) without or with FPS‐ZM1 (100 μM, receptor for advanced endglycation products [RAGE]‐specific inhibitor) and endothelial function (acetylcholine dilator response) was compared to baseline control. Medin's effect on adipose arteriole smooth muscle function was tested by comparing post‐exposure dilator response to DETA NONOate (a nitric oxide [NO] donor) compared to baseline response. Human umbilical vein endothelial cells were exposed to medin (20 hours) without or with FPS‐ZM1 and oxidative and nitrative stress, cell viability and pro‐inflammatory signaling measures were obtained. Medin caused impaired endothelial function (versus baseline response to 10 −4 M acetylcholine: −38.6±6.7% and −35.0±8.9% in adipose and leptomeningeal arterioles, respectively, each p<0.05) in human adipose and leptomeningeal arterioles. Medin did not affect adipose arteriole dilator response to DETA NONOate. Medin‐induced endothelial dysfunction was reversed by RAGE inhibitor. Medin decreased endothelial cell NO production and cell viability, increased peroxynitrite, superoxide production and profoundly 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). These effects were reversed by RAGE inhibitor. Conclusions Medin causes human microvascular endothelial dysfunction, oxidative and nitrative stress and pro‐inflammatory signaling mediated via RAGE. The discovery of this novel mechanism of injury may have implications in our understanding of and development of treatments to reverse vascular aging. Support or Funding Information The work was supported by National Institutes Health (NIA R21AG044723, NINDS U24NS072026, NIA P30AG19610, NIA RO1AG019795); Veterans Affairs Merit grant (I01BX007080); British Heart Foundation (FS/12/61/29877); the Arizona Department of Health Services (contrast 211002); the Arizona Biomedical Research Commission (4001, 0011, 05‐901 and 1001); Michael J. Fox Foundation for Parkinson's Research and Amyloidosis Foundation. The study was based on work supported by the Department of Veterans Affairs and VA employment.