Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation

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.

Keywords: CLU; Clusterin; Diabetes; Endothelial dysfunction; Mitochondrial fission; Oxidative stress.