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

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

doi:10.1093/cvr/cvx135

Cited by 35 publications

(46 citation statements)

References 42 publications

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“…4 ), indicative of the formation of medin membrane pores. These results open the possibility to the presence of medin-induced unregulated ionic currents through the plasma membrane, which could alter cellular ionic homeostasis and lead to the endothelial dysfunction and medin-induced EC cytotoxicity observed in vitro ( 33 ).…”

Section: Discussionmentioning

confidence: 98%

“…Medin is the main constituent of AMA, the most common form of localized amyloid ( 20 ). Little is known about its exact in vivo pathological role; however, ex vivo evidence suggests medin is implicated in multiple cardiovascular disorders ( 28 , 29 , 30 , 31 ), including vascular contributions to neurodegeneration ( 33 , 34 ) and vascular dementia ( 32 ). An in vivo study found higher abundance of nonamyloidogenic medin species in aortas from patients with either thoracic aortic aneurysms or aortic dissection than in control individuals with normal aortas ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…We also showed that physiologic doses of medin induce endothelial dysfunction, endothelial cell (EC) immune activation, and cytotoxicity ( 33 ), which appear to enhance neuroinflammation ( 32 ), pointing to medin’s potential role in the pathophysiology of cerebrovascular disease and vascular dementia. Importantly, both medin and A β induce profound endothelial dysfunction and oxidative stress in human arterioles ( 33 , 34 ), suggesting a potential for in vivo interactions between both amyloids. Our previous ex vivo experiments suggest that medin-induced EC oxidative stress is a potential mechanism of EC dysfunction ( 35 ); however, the underlying mechanisms of medin-induced pathology remain poorly understood and have rarely been addressed ( 35 ).…”

Section: Introductionmentioning

confidence: 94%

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Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction

Younger

Jang

Davies

et al. 2020

Biophysical Journal

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Medin, a 50-amino-acid cleavage product of the milk fat globule-EGF factor 8 protein, is one of the most common forms of localized amyloid found in the vasculature of individuals older than 50 years. Medin induces endothelial dysfunction and vascular inflammation, yet despite its prevalence in the human aorta and multiple arterial beds, little is known about the nature of its pathology. Medin oligomers have been implicated in the pathology of aortic aneurysm, aortic dissection, and more recently, vascular dementia. Recent in vitro biomechanical measurements found increased oligomer levels in aneurysm patients with altered aortic wall integrity. Our results suggest an oligomer-mediated toxicity mechanism for medin pathology. Using lipid bilayer electrophysiology, we show that medin oligomers induce ionic membrane permeability by pore formation. Pore activity was primarily observed for preaggregated medin species from the growth-phase and rarely for lag-phase species. Atomic force microscopy (AFM) imaging of medin aggregates at different stages of aggregation revealed the gradual formation of flat domains resembling the morphology of supported lipid bilayers. Transmission electron microscopy images showed the coexistence of compact oligomers, largely consistent with the AFM data, and larger protofibrillar structures. Circular dichroism spectroscopy revealed the presence of largely disordered species and suggested the presence of β -sheets. This observation and the significantly lower thioflavin T fluorescence emitted by medin aggregates compared to amyloid- β fibrils, along with the absence of amyloid fibers in the AFM and transmission electron microscopy images, suggest that medin aggregation into pores follows a nonamyloidogenic pathway. In silico modeling by molecular dynamics simulations provides atomic-level structural detail of medin pores with the CN p NC barrel topology and diameters comparable to values estimated from experimental pore conductances.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction

Younger

Jang

Davies

et al. 2020

Biophysical Journal

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“…In ex vivo human adipose and leptomeningeal arterioles, the protein could decrease NO production, increase peroxynitrite, and superoxide production and enhance the expression of the proinflammatory markers such as IL-6 and IL-8 as well as the NF-κB transcription factor. These effects were shown to be mediated through RAGE and inhibition of RAGE by its specific inhibitor, FPS-ZM1, could reverse all such changes [ 50 ].…”

Section: Biology Of the Endothelium And Endothelial Dysfunctionmentioning

confidence: 99%

Role of free fatty acids in endothelial dysfunction

et al. 2017

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Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.

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“…Vascular endothelium is a layer of monocytes on the inner walls of blood vessels, regulating vascular wall function via autocrine and paracrine system. Human vascular endothelial dysfunction is caused by oxidative stress and promoted inflammatory signaling in endothelial cells (Migrino et al 2017). Importantly, vascular inflammation is a main initial effect to induce atherosclerosis that is a complex vascular injury.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-like protein 7 mediates TNF-α-induced adhesion and oxidative stress in human umbilical vein epithelial cells

Liang²,

Wang³

et al. 2020

gpb

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Tumor necrosis factor-α (TNF-α) promotes monocyte adhesion to endothelium and accumulation of endothelium will lead to atherosclerosis. The present study explored angiopoietin-like protein (Angptl7) as a potential target in the process of atherosclerosis, and its role in the adhesion and oxidative stress induced by TNF-α in human umbilical vein epithelial cells (HUVEC). The initiation of atherosclerosis is endothelial injury. Angptl7 was dramatically increased in TNF-α-induced HUVEC compared to the control cells. After Angptl7 effectively knocked-down in TNF-α-induced HUVEC, the levels of reactive oxygen species (ROS), interleukin (IL)-1β, IL-6 and cyclooxygenase-2 (Cox-2) were prominently decreased, whereas the levels of nitric oxide (NO) and endothelia nitric oxide synthase (eNOS) were increased. Inhibition of Angptl7 significantly reversed TNF-α-induced cell adhesion in HUVEC. Finally, downregulation of Angptl7 significantly reduced the expression of nuclear factor-κB (NF-κB) and enhanced the levels of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) in TNF-α-treated HUVEC. Angptl7 conducted TNF-αinduced oxidative stress and cell adhesion in HUVEC. Therefore, Angptl7 might participate in the development of endothelial injury and further atherosclerosis. This might give us a new insight for investigation of procession of atherosclerosis.

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

Abstract: 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.

Cited by 35 publications

References 42 publications

Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction

Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction

Role of free fatty acids in endothelial dysfunction

Angiopoietin-like protein 7 mediates TNF-α-induced adhesion and oxidative stress in human umbilical vein epithelial cells

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