CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis

Hong Shi, Chao Zhang, Vinay Pasupuleti, Xingjian Hu, Domenick A. Prosdocimo, Wenconghui Wu, Yulan Qing, Shitong Wu, Haneen Mohammad, Stanton L. Gerson, Bernard Perbal, Philip A. Klenotic, Nianguo Dong, Zhiyong Lin

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1230-1237
Number of pages8
JournalAmerican Journal of Pathology
Issue number6
StatePublished - Jun 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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