Atherosclerosis is the result of both lipid deposition and chronic vascular inflammation. However, a defined causal role for inflammation in atherogenesis is elusive, largely because of the lack of a clinical success of anti- inflammatory agents in atherosclerosis control. Nevertheless, evidence of the participation of the immune system, especially the key components of innate immunity, Toll-like receptors (TLRs), holds strong in experimental atherosclerosis. Over a dozen TLRs have been identified so far, most of them expressed in atheroma cells, with TLR2 and TLR4 being best documented. Blockade of TLR2 and TLR4 signaling is an intriguing therapeutic approach for atherosclerosis. However, the development of TLR antagonists as therapeutic agents has been surprisingly slow, and no TLR2 or TLR4 antagonists are currently approved for clinic use. Recently, we identified a natural compound Sparstolonin B (SsnB) as an antagonist for TLR2 and TLR4. Our recently published data and new preliminary studies show that: 1) SsnB has potent anti-inflammatory effects on macrophages by selectively blocking TLR2 and TLR4 signaling;2) SsnB interrupts the recruitment of MyD88 to TLR2 and TLR4;3) SsnB diminishes the ability of activated arterial endothelial cells to attract monocytes, and decreases arterial smooth muscle cell migration;and 4) SsnB effectively suppresses inflammatory response to lipopolysaccharide in mice. On the basis of these data, we hypothesize that SsnB can attenuate atherogenesis by virtue of its inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose three specific aims: SA1. To test the hypothesis that SsnB attenuates atherogenesis in mice;SA2. To test the hypothesis that SsnB mitigates inflammation in vascular cells by blocking TLR2 and TLR4 signaling;and SA3. To determine the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. The confirmation of the hypothesis will usher the development of SsnB as a new anti-atherogenic agent;it will also provide a pharmacological evidence for the causal role of TLR2 and TLR4 signaling in atherogenesis.

Public Health Relevance

Atherosclerosis is an inflammatory disease and a primary cause of heart attack and stroke. Toll-like receptor (TLR) 2 and TLR4 play detrimental roles in atherogenesis. We have identified a natural compound Sparstolonin B as a selective TLR2 and TLR4 antagonist. The confirmation of the hypothesis in this study that Sparstolonin B can attenuate atherogenesis will usher the development of this compound as a new anti-atherogenic therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Carolina at Columbia
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Cao, Jia; Xu, Yanyong; Li, Feifei et al. (2018) Protein markers of dysfunctional HDL in scavenger receptor class B type I deficient mice. J Transl Med 16:155
Li, Yong; Huang, Xuan; Huang, Shengping et al. (2017) Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury. Signal Transduct Target Ther 2:17066
Sergin, Ismail; Evans, Trent D; Zhang, Xiangyu et al. (2017) Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nat Commun 8:15750
Jones, Rebecca S; Chang, Pin H; Perahia, Tzlil et al. (2017) Design and Fabrication of a Three-Dimensional In Vitro System for Modeling Vascular Stenosis. Microsc Microanal 23:859-871
Leng, Shuilong; Iwanowycz, Stephen; Saaoud, Fatma et al. (2016) Ursolic acid enhances macrophage autophagy and attenuates atherogenesis. J Lipid Res 57:1006-16
Wang, Junfeng; Iwanowycz, Stephen; Yu, Fang et al. (2016) microRNA-155 deficiency impairs dendritic cell function in breast cancer. Oncoimmunology 5:e1232223
He, Hui; Guo, Fang; Li, Yong et al. (2016) Adiporedoxin suppresses endothelial activation via inhibiting MAPK and NF-?B signaling. Sci Rep 6:38975
Iwanowycz, Stephen; Wang, Junfeng; Altomare, Diego et al. (2016) Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory. J Biol Chem 291:11491-503
Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie et al. (2016) Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages. Mol Cancer Ther 15:1931-42
Xu, Yanyong; Liu, Hongmei; Liu, Mengting et al. (2016) A human apolipoprotein E mimetic peptide reduces atherosclerosis in aged apolipoprotein E null mice. Am J Transl Res 8:3482-92

Showing the most recent 10 out of 28 publications