Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation, 2019, Ren et al

Andy · Oct 16, 2019

Highlights

• Clusterin overexpression rescues diabetes-induced endothelial dysfunction.
• In diabetic models, clusterin inhibits oxidative stress and mitochondrial ROS production.
• Clusterin suppresses mitochondrial fragmentation via reducing expression level of Drp-1.
• AMPK activation involved in the molecular mechanisms of clusterin against endothelial dysfunction.

Abstract
Clusterin (CLU) is a stress-responding protein associated with cytoprotection in a broad range of pathological processes. However, clusterin's function in diabetes-induced endothelial dysfunction has not been defined. Herein, using two diabetes models, we investigated the role of clusterin in endothelial dysfunction triggered by diabetes and the molecular mechanisms involved. The results revealed that clusterin overexpression inhibited ICAM-1/VCAM-1 expression in aortas and improved endothelium-dependent vasodilatation in db/db diabetic mice and streptozotocin (STZ)-induced diabetes models. Consistently, in vitro, adenoviral clusterin overexpression reduced the expression of a range of pro-inflammatory cytokines and suppressed monocyte adhesion to endothelial cells subjected to high glucose and high palmitate. Further study indicated that clusterin overexpression mitigated mitochondrial excessive fission and reduced mitochondrial ROS production. Conversely, silencing clusterin aggravated mitochondrial fission and endothelial inflammatory activation in high glucose-exposed endothelial cells. Accumulating evidence indicates that impaired mitochondrial dynamics plays a considerable role in promoting endothelial dysfunction in diabetic subjects. Therefore, treatments targeting mitochondrial undue fission may be promising measures to prevent vascular complications of diabetes. Furthermore, AMP-activated protein kinase (AMPK) activation contributed to the modulation of mitochondrial dynamics executed by clusterin. Mechanistically, clusterin promoted the phosphorylation of AMPKα and its downstream target acetyl-CoA carboxylase (ACC), while the inhibition of AMPKα negated the improvement in mitochondrial dynamics provided by clusterin overexpression. Over all, these findings suggest that clusterin exerts beneficial effects in endothelial cells under diabetic conditions via inhibiting mitochondrial fragmentation mediated by AMPK.
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Paywall, https://www.sciencedirect.com/science/article/abs/pii/S0891584919312730
Scihub, https://sci-hub.se/10.1016/j.freeradbiomed.2019.10.008

mariovitali · Oct 16, 2019

It is also interesting to see ICAM-1 there (something on Machine Learning's Radar for some time).

I wanted to find why humidity has been affecting me so negatively and was looking to understand the mechanism. Keeping in mind ICAM-1 shown on @Andy 's post above :

Effects of Temperature and Relative Humidity on DNA Methylation
Marie-Abele Bind,a,b Antonella Zanobetti,a Antonio Gasparrini,c Annette Peters,a,d Brent Coull,b Andrea Baccarelli,a Letizia Tarantini,e Petros Koutrakis,a Pantel Vokonas,f and Joel Schwartza
Author information Copyright and License information Disclaimer

Interactions Between Temperature and Relative Humidity
We investigated whether exposures to temperature and relative humidity (3 week) interact to modify levels of ICAM-1 and LINE-1 methylation. After fitting a 2-dimensional smoothing of temperature and relative humidity on ICAM-1 methylation, we obtained a 3D surface that indicated an interaction between temperature and relative humidity during humid and hot days (Figure 1). The relative humidity association with ICAM-1 methylation was stronger during hot days (Figure 2). We did not find any evidence of an interaction between temperature and relative humidity that modified LINE-1 methylation.

<SNIP>

Results
Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5°c increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (−8% to −1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days.
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Unfortunately, i do not know if this connection makes sense biologically-wise.

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Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation, 2019, Ren et al

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Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation, 2019, Ren et al

Andy Committee Member

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