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Cardiovasc Res. 2015 Sep 1;107(4):556-67. doi: 10.1093/cvr/cvv178. Epub 2015 Jun 19.

Cross-talk between LOX-1 and PCSK9 in vascular tissues.

Author information

1
Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
2
Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China sliu2@uams.edu mehtajl@uams.edu.
3
Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
4
Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
5
Department of Physiology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan.
6
Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA sliu2@uams.edu mehtajl@uams.edu.

Abstract

AIMS:

Lectin-like ox-LDL receptor-1 (LOX-1) plays an important role in inflammatory diseases, such as atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates LDL receptor degradation and influences serum LDL levels. The present study was designed to investigate the possible interaction between PCSK9 and LOX-1.

METHODS AND RESULTS:

In the first set of experiments, human vascular endothelial cells and smooth muscle cells were studied at baseline and after lipopolysaccharide (LPS) treatment (to create an inflammatory state). Both PCSK9 and LOX-1 were strongly induced by LPS treatment. To define the role of PCSK9 in LOX-1 expression, cells were transfected with siRNA against PCSK9, which resulted in reduced LOX-1 expression and function. On the other hand, cells exposed to recombinant hPCSK9 revealed enhanced LOX-1 expression (P < 0.05). To determine whether LOX-1 also regulates PCSK9, cultured cells in which LOX-1 was knocked down by siRNA expressed less PCSK9, whereas those transfected with hLOX-1 cDNA showed increased PCSK9 expression. The second set of experiments was carried out in wild-type (WT) and gene knockout (KO; LOX-1 and PCSK9) mice; LOX-1 KO mice showed much less PCSK9 (P < 0.05 vs. WT mice). PCSK9-KO mice showed much less LOX-1 (P < 0.05 vs. WT mice). Furthermore, we observed that mitochondrial reactive oxygen species (mtROS) plays an initiating role in the LOX-1/PCSK9 interaction, since mtROS induction enhanced and its inhibition reduced the expression of both PCSK9 and LOX-1. We also found that both LOX-1 and PCSK9 regulate adhesion molecules vascular cell adhesion molecule-1 expression. Finally, oxidized low-density lipoprotein and tumour necrosis factor-α, pro-inflammatory stimuli besides LPS, regulated PCSK9 expression that is mediated by the NF-κB signalling pathway.

CONCLUSIONS:

These observations suggest that LOX-1 and PCSK9 positively influence each other's expression, especially during an inflammatory reaction. mtROS appear to be important initiators of PCSK9/LOX-1 expression.

KEYWORDS:

LOX-1; Mitochondrial ROS; PCSK9; VCAM-1

PMID:
26092101
DOI:
10.1093/cvr/cvv178
[Indexed for MEDLINE]

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