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Published on: September 26, 2018
Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced
Raymond Q Migrino1,2, Hannah A Davies3, Seth Truran1
1Office of Research, Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85022, USA.
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.
Insights
Medin protein impairs human arteriole endothelial function by increasing oxidative stress and inflammation, potentially via the receptor for advanced glycation endproducts (RAGE). These findings reveal a novel mechanism for vascular injury.
Area of Science:
- Vascular Biology
- Endothelial Function
- Protein Biochemistry
Background:
- Medin is an amyloidogenic protein found in human arteries, linked to vascular degeneration.
- The impact of medin on endothelial function is not well understood.
- Investigating medin's role is crucial for understanding age-related vascular changes.
Purpose of the Study:
- To determine medin's effects on human arteriole endothelial function.
- To elucidate the mechanisms behind medin-induced vascular injury.
- To explore the role of the receptor for advanced glycation endproducts (RAGE) in medin's vascular effects.
Main Methods:
- Ex vivo analysis of human adipose and leptomeningeal arterioles exposed to medin.
- Assessment of endothelium-dependent (acetylcholine) and independent (nitric oxide donor) responses.
- In vitro studies on human umbilical vein endothelial cells measuring oxidative stress, viability, and inflammatory markers.
- Evaluation of medin's effects with and without RAGE inhibitor FPS-ZM1.
Main Results:
- Medin significantly impaired endothelial function in human arterioles.
- Medin reduced nitric oxide production and endothelial cell viability while increasing superoxide production.
- Medin upregulated pro-inflammatory cytokines (interleukin-6, interleukin-8) via NFκB activation.
- RAGE inhibition and antioxidant treatment reversed medin-induced endothelial dysfunction and oxidative stress.
Conclusions:
- Medin induces human microvascular endothelial dysfunction.
- Oxidative stress, nitrative stress, and pro-inflammatory signaling mediate medin's effects.
- The receptor for advanced glycation endproducts (RAGE) appears to be a key mediator of medin-induced vascular injury.
- These findings suggest a novel mechanism contributing to vascular damage.
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