Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis
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Kayashima, Yukako, et al. Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis. 2022. https://doi.org/10.17615/37zt-x391APA
Kayashima, Y., Clanton, C., Lewis, A., Sun, X., Hiller, S., Huynh, P., Wilder, J., Hagaman, J., Li, F., Maeda Smithies, N., & Harris, E. (2022). Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis. https://doi.org/10.17615/37zt-x391Chicago
Kayashima, Yukako, Connor A Clanton, Amanda M Lewis, Xinghui Sun, Sylvia Hiller, Phillip Huynh, Jennifer Wilder et al. 2022. Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis. https://doi.org/10.17615/37zt-x391- Creator
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Kayashima, Yukako
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Clanton, Connor A.
- Other Affiliation: University of Nebraska
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Lewis, Amanda M.
- Other Affiliation: University of Nebraska
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Sun, Xinghui
- Other Affiliation: University of Nebraska
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Hiller, Sylvia
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Huynh, Phillip
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Wilder, Jennifer
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Hagaman, John
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Li, Feng
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Maeda-Smithies, Nobuyo
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Harris, Edward N.
- Other Affiliation: University of Nebraska
- 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 Stab2DBA 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 STAB2DBA 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.
- Date of publication
- 2022
- Keyword
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- Frontiers in Cardiovascular Medicine
- Journal volume
- 9
- Language
- English
- Version
- Publisher
- ISSN
- 2297-055X
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