TY - JOUR
T1 - CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis
AU - Shi, Hong
AU - Zhang, Chao
AU - Pasupuleti, Vinay
AU - Hu, Xingjian
AU - Prosdocimo, Domenick A.
AU - Wu, Wenconghui
AU - Qing, Yulan
AU - Wu, Shitong
AU - Mohammad, Haneen
AU - Gerson, Stanton L.
AU - Perbal, Bernard
AU - Klenotic, Philip A.
AU - Dong, Nianguo
AU - Lin, Zhiyong
N1 - Funding Information:
Supported by NIH grants HL087595, HL117759, and AA021390 (all to Z.L.), the National Natural Science Foundation of China grant 81600345 (C.Z.), and the National Key Research and Development Program of China Stem Cell and Translational Research grant 2016YFA0101100 (N.D.).
PY - 2017/6
Y1 - 2017/6
N2 - Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe−/− background developed increased aortic lipid-rich plaques compared to control Apoe−/− mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe−/− mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe−/− marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow–derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.
AB - Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe−/− background developed increased aortic lipid-rich plaques compared to control Apoe−/− mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe−/− mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe−/− marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow–derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.
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U2 - 10.1016/j.ajpath.2017.01.020
DO - 10.1016/j.ajpath.2017.01.020
M3 - Article
C2 - 28527710
AN - SCOPUS:85019579419
VL - 187
SP - 1230
EP - 1237
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -