Identification of Novel Gene Chondroitin Sulfate N-Acetylgalactosaminyl-transferase 2 in Atherosclerotic Plaque Formation

[Speaker] Imam M. Adhikara:1
[Co-author] Keiko Yagi:2, Yoko Suzuki:1, Kazuya Miyagawa:2, Koji Ikeda:2, Ken-Ichi Hirata:1, Noriaki Emoto:2
1:Department of Internal Medicine, Division of Cardiovascular Medicine, Kobe University, Japan, 2:Department of Clinical Pharmacy, Kobe Pharmaceutical University, Japan

Background: Response-to-retention theory suggested that retention of lipoprotein (LDL) in the intimal layer of arterial wall hallmarks the early phase of atherosclerosis. Glycosaminoglycans (GAG) of proteoglycans in the extracellular matrix (ECM) are postulated to have an important role on LDL retention. N-acetylgalactosaminyl-transferase-2 (ChGn-2) is a member of GAG synthetizing enzymes; our previous study revealed that ChGn-2 expression is upregulated during atherosclerosis. Nonetheless, the role of ChGn-2 on LDL retention and atherosclerotic plaque formation has not been elucidated.

Methods: We investigated the role of ChGn-2 on the development of atherosclerosis by generating ChGn-2-/-/LDLr-/- mice. Plaque formation and GAG contents were visualized using Oil red O and alcian blue staining respectively. Thioglycollate-elicited peritoneal macrophage (TEPM) and smooth muscle cell (SMC) derived from ChGn-2-/- mice were treated with LDL and phenotype changes were observed.

Results: ChGn-2-/-/LDLr-/- mice generated less atherosclerotic plaque after fed with western diet despite its similar metabolic phenotype in comparison with its ChGn-2+/+/LDLr-/- littermates. Interestingly, foam cell formation was significantly altered by ChGn-2 in macrophages and ChGn-2 insinuated aortic SMC phenotypic changes. Consequently, ChGn-2 alteration on macrophage and SMC conceivably influences LDL accumulation and subsequently initiates plaque formation.

Conclusions: These results collectively suggest that ChGn-2 is a novel therapeutic target in the future amenable for clinical translation.

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