Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis

Ian Ackers; Candice Szymanski; K Jordan Duckett; Leslie A Consitt; Mitchell J Silver; Ramiro Malgor

doi:10.1016/j.carpath.2018.01.008

Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis

Cardiovasc Pathol. 2018 May-Jun:34:1-8. doi: 10.1016/j.carpath.2018.01.008. Epub 2018 Feb 21.

Authors

Ian Ackers¹, Candice Szymanski², K Jordan Duckett², Leslie A Consitt³, Mitchell J Silver⁴, Ramiro Malgor⁵

Affiliations

¹ Heritage Fellow, Translational Biomedical Sciences Program, Ohio University, Athens, Ohio, USA.
² Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
³ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA; The Diabetes Institute, Ohio University, Athens, Ohio, USA.
⁴ Midwest Cardiology Research Foundation, Columbus, Ohio, USA.
⁵ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA; The Diabetes Institute, Ohio University, Athens, Ohio, USA; Molecular and Cellular Biology Graduate Program, Ohio University, Athens, Ohio, USA. Electronic address: malgor@ohio.edu.

PMID: 29474941
DOI: 10.1016/j.carpath.2018.01.008

Abstract

Background and aims: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells.

Methods: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining.

Results: Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01).

Conclusions: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells.

Keywords: Atherosclerosis; Box5; CD36; Foam cell; Wnt5a.

MeSH terms

Atherosclerosis / drug therapy*
Atherosclerosis / metabolism
Atherosclerosis / pathology
CD36 Antigens / metabolism*
Foam Cells / drug effects*
Foam Cells / metabolism
Foam Cells / pathology
Frizzled Receptors / metabolism
Humans
Lipid Metabolism / drug effects
Oligopeptides / pharmacology*
Plaque, Atherosclerotic
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Signal Transduction / drug effects
THP-1 Cells
Time Factors
Wnt-5a Protein / antagonists & inhibitors*
Wnt-5a Protein / metabolism

Substances

CD36 Antigens
FZD5 protein, human
Frizzled Receptors
N-butyloxycarbonyl-methionyl-aspartyl-glycyl-cysteinyl-glutamyl-leucine
Oligopeptides
WNT5A protein, human
Wnt-5a Protein
ROR2 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors