Reduction of Stabilin-2 Contributes to a Protection Against AtherosclerosisStabilin

Authors

Yukako Kayashima1*,, University of North Carolina at Chapel Hill
Conner A. Clanton, University of Nebraska - Lincoln
Amanda M. Lewis, University of Nebraska - Lincoln
Xinghui Sun, University of Nebraska - LincolnFollow
Sylvia Hiller, University of North Carolina at Chapel Hill
Phillip Huynh, University of North Carolina at Chapel Hill,
Jennifer Wilder, University of North Carolina at Chapel Hill
John Hagaman, University of North Carolina at Chapel Hill
Feng Li, University of North Carolina at Chapel Hill
Nobuyo Maeda-Smithies, University of North Carolina at Chapel Hill
Edward N. Harris, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

3-11-2022

Citation

Kayashima Y, Clanton CA, Lewis AM, Sun X, Hiller S, Huynh P, Wilder J, Hagaman J, Li F, Maeda-Smithies N and Harris EN (2022) Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis. Front. Cardiovasc. Med. 9:818662. doi: 10.3389/fcvm.2022.818662

Comments

open access

Abstract

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe^−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe^−/− mice carrying Aath5 covering the Stab2^DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2^−/−Apoe^−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2^−/−Apoe^−/− males developed approximately 30% smaller plaques than Stab2^+/+Apoe^−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2^−/−Apoe^−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2¹²⁹ or STAB2^DBA proteins, as well as STAB2¹²⁹ proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing ¹²⁵I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele.