Imam Manggalya Adhikara1,2, Keiko Yagi1, Dyah Samti Mayasari1,2, Yoko Suzuki1,2, Koji Ikeda1, Gusty Rizky Teguh Ryanto1,2, Naoto Sasaki3, Yoshiyuki Rikitake3, Satomi Nadanaka4, Hiroshi Kitagawa4, Okiko Miyata5, Michihiro Igarashi6, Ken-Ichi Hirata2, Noriaki Emoto1,2. 1. Laboratory of Clinical Pharmaceutical Science (I.M.A., K.Y., D.S.M., Y.S., K.I., G.R.T.R., N.E.), Kobe Pharmaceutical University, Japan. 2. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan (I.M.A., D.S.M., Y.S., G.R.T.R., K.-i.H., N.E.). 3. Laboratory of Medical Pharmaceutics (N.S., Y.R.), Kobe Pharmaceutical University, Japan. 4. Laboratory of Biochemistry (S.N., H.K.), Kobe Pharmaceutical University, Japan. 5. Laboratory of Medicinal Chemistry (O.M.), Kobe Pharmaceutical University, Japan. 6. Department of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Japan (M.I.).
Abstract
OBJECTIVE: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated. CONCLUSIONS: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.
OBJECTIVE:Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results:ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated. CONCLUSIONS:ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.