Highlights
- •RBP4 deteriorates endothelial mitochondrial function and promotes vascular oxidative stress.
- •RBP4 breaks the homeostasis of fusion and fission in mitochondria.
- •RBP4-induced apoptosis in endothelial cells is PI3K/Akt dependent.
Abstract
Objectives
Mitochondrial dysfunction has been implicated in cardiovascular diseases. Elevation
of serum retinol binding protein 4 (RBP4) in patients has been linked to cardiovascular
disease. However, the role of RBP4 on mitochondrial oxidative stress and vascular
oxidative damage is not well demonstrated. Therefore, we evaluated the impact of RBP4
on the mitochondrial reactive oxygen species (ROS) and dynamics in the pathogenesis
of cardiovascular diseases.
Methods and results
RBP4 treatment increased mitochondrial superoxide generation in a dose-dependent manner
in human aortic endothelial cells (HAECs). Exposure to RBP4 also promoted mitochondrial
dysfunction as determined by decreased mitochondrial content and integrity as well
as membrane potential in HAECs. Incubation with RBP4 suppressed mitofusin (Mfn)-1
protein expression, but enhanced dynamin-related protein-1 (Drp1) and fission-1 (Fis1)
protein expression in HAECs, suggesting an impairment of mitochondrial fusion and
fission dynamics. Moreover, RBP4 treatment significantly induced endothelial apoptosis,
increased the expression of Cytochrome C and Bax, but decreased the expression of
Bcl-2. Furthermore, RBP4 stimulation suppressed phosphatidyl inositol 3-kinase (PI3K)/Akt
signaling in HAECs. Finally, RBP4-Tg mice exhibited severe mitochondrial dysfunction
and vascular oxidative damage in aorta compared with wide-type C57BL/6J mice.
Conclusion
The present study uncovers a novel mechanism through which RBP4 induces vascular oxidative
damage and accelerates the development of atherosclerosis.
Keywords
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Article info
Publication history
Published online: March 28, 2015
Accepted:
March 25,
2015
Received in revised form:
March 8,
2015
Received:
November 15,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
