Atherosclerosis is evoked by both lipid deposition and chronic vascular inflammation, in which monocytes/macrophages play critical roles. The recent identification of heterogeneity of circulating monocytes and lesional macrophages has provided new insights into the mechanism underlying the involvement of monocytes/macrophages in atherogenesis. An emerging notion is that in the presence of systemic pro-atherogenic stress (i.e., hyperlipidemia and inflammation), some circulating monocytes acquire distinct pro-inflammatory phenotypes that prime them to infiltrate the arterial wall and give rise to a pro-inflammatory macrophage subset within the plaque. MicroRNAs (miRs) are short non-coding RNA molecules capable of regulating gene expression by targeting mRNAs, resulting in translational repression or mRNA degradation. They play essential roles in multiple biological and pathological processes, thus emerging as new targets for diagnosis and therapy of several human diseases. One miR, miR155, has been demonstrated to play a crucial role in immune response regulation. Recent studies have shown that miR155 expression in monocytes and macrophages is up-regulated upon stimulation with various ligands for toll-like receptors (TLRs), and it may exaggerate monocyte and macrophage inflammation by targeting several negative regulators of TLR-mediated signaling. While TLRs and their ligands are fundamentally involved in atherogenesis, the contribution of monocyte/macrophage miR155 to atherosclerosis has not been investigated. Our preliminary studies suggest a potential role of monocyte/macrophage miR155 in atherosclerosis, and prompt us to hypothesize that up-regulation of miR155 expression is an integral feature of the pro-atherogenic phenotype of circulating monocytes.
Two specific aims are proposed to test this hypothesis. SA1. To test the hypothesis that miR155 expression is up-regulated in circulating monocytes of atherosclerotic mice. We will measure miR155 expression in circulating monocytes using two hypercholesterolemic mouse models, evaluate its correlation with lesion size, plasma lipids, and inflammatory markers, and examine whether miR155 is differentially expressed in circulating monocyte subsets. SA2. To test the hypothesis that increased miR155 expression represents a pro-atherogenic phenotype of monocytes. We will transduce monocytes isolated from mice with lentiviral vectors to introduce miR155 overexpression or inhibition, and test the effects of miR155 manipulation on monocyte adhesion to aortic endothelium, infiltration into intima and foam cell transformation. We will also explore the underlying molecular mechanism.

Public Health Relevance

Atherosclerosis is the direct cause of heart attack and stroke, the No. 1 and No. 3 killers in the United States. There is an urgent call for more sensitive noninvasive diagnostic tools to detect patients at high risk of clinical events as well as for developing effective and safe anti-inflammation therapies to complement cholesterol-lowering therapy for atherosclerosis. The identification of miR155 as a pro- atherogenic feature of circulating monocytes holds the potential to significantly impact future clinical practice.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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
Wang, Junfeng; Yu, Fang; Jia, Xuemei et al. (2015) MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth. Int J Cancer 136:E602-13
Du, Fen; Yu, Fang; Wang, Yuzhen et al. (2014) MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 34:759-67
Guan, Hongbing; Fan, Daping; Mrelashvili, Davit et al. (2013) MicroRNA let-7e is associated with the pathogenesis of experimental autoimmune encephalomyelitis. Eur J Immunol 43:104-14
Yu, Fang; Du, Fen; Wang, Yuzhen et al. (2013) Bone marrow deficiency of MCPIP1 results in severe multi-organ inflammation but diminishes atherogenesis in hyperlipidemic mice. PLoS One 8:e80089
Yu, Fang; Jia, Xuemei; Du, Fen et al. (2013) miR-155-deficient bone marrow promotes tumor metastasis. Mol Cancer Res 11:923-36
Huang, Shengping; Qi, Dongfei; Liang, Jian et al. (2012) The putative tumor suppressor Zc3h12d modulates toll-like receptor signaling in macrophages. Cell Signal 24:569-76
Du, Fen; Hui, Yvonne; Zhang, Michelle et al. (2011) Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 286:43054-61
Qi, Dongfei; Huang, Shengping; Miao, Ruidong et al. (2011) Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J Biol Chem 286:41692-700