Suppression of vascular endothelial cell inflammation Both adaptive and innate immunity tightly regulate atherosclerosis. Vascular endothelial cells (ECs) are targets of proinflammatory cytokines, such as interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a). However, the important question of whether ECs play a critical role in initiating vascular inflammation remains poorly defined. In particular, the issue of whether ECs in atherogenic conditions generate excess IL-1b via the newly-defined inflammasome remains unknown. Therefore, the goal of this proposal is to examine a novel hypothesis that EC inflammation with the generation of IL-1b followed by EC apoptosis is accelerated in the pathogenesis of atherosclerosis. The corollary hypothesis is that factors and cells in suppressing EC generation of excess IL- 1b and EC apoptosis play inhibitory roles in atherogenesis. Preliminary data from our lab and reports from others'labs clearly support this hypothesis: (i) Microbial infections play a role in the pathogenesis of atherosclerosis. In response to the stimulation of bacterial lipopolysaccharide (LPS), mouse aortic ECs (MAECs) from atherogenic apolipoprotein E-deficient ApoE-/- mice express higher levels of pro-IL-1b than MAECs from wild-type control mice. The upregulation of pro-IL-1b in MAECs from ApoE-/- mice is increased in the presence of phosphatidylinositol 3-kinase (PI-3K) inhibitors Wortmannin and Ly294002, suggesting that PI3K-Akt survival pathway suppresses IL-1b-generating EC inflammation;(ii) We have identified a novel Bcl-xL interacting, anti-apoptotic protein TCTP. TCTP is an important regulator and anti-apoptotic protein along PI3K- Akt survival pathway. In addition, TCTP is also down-regulated in response to LPS stimulation in ECs, suggesting that anti-TCTP may inhibit EC inflammation and apoptosis as a PI-3K-Akt pathway-signaled protective mechanism of ECs. In addition, we found that co-culture of MAECs from ApoE-/- mice with CD4+CD25highFoxp+ regulatory T cells (Tregs) results in decreased pro-IL-1b expression in response to LPS, suggesting that immunosuppressive Tregs suppress EC inflammation;(iii) IL-1b deficiency inhibits EC inflammation and atherogenesis. Therefore, the elucidation of the suppressive mechanisms of IL-1b-generating EC inflammation and EC apoptosis is clinically significant, as it may lead to new therapeutics for treating atherosclerosis and vascular inflammation. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-1b-generating EC inflammation is accelerated in atherogenic ApoE-/- mice in comparison to that in wild-type control mice;(2) To determine whether TCTP and PI3K-Akt intracellular signaling pathway inhibits IL-1b-generating EC inflammation and EC apoptosis in ApoE-/- mice; and (3) To determine whether extracellular suppression of IL-1b-generating EC inflammation and EC apoptosis by Tregs attenuates the atherogenesis in ApoE-/- mice.

Public Health Relevance

There is increasing evidence that vascular endothelial cell (ECs) inflammation significantly contributes to the development of atherosclerosis. However, the important question of whether ECs play a critical role in initiating vascular inflammation remains poorly defined. The proposed studies will provide better understanding whether the elucidation of the suppressive mechanisms of IL-1b-generating EC inflammation and EC apoptosis can lead to the development of new therapeutics for treating atherosclerosis and vascular cell inflammation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-F (03))
Program Officer
Olive, Michelle
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Schools of Medicine
United States
Zip Code
Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2017) Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. Can J Physiol Pharmacol 95:247-252
Xu, Yanjie; Xia, Jixiang; Liu, Suxuan et al. (2017) Endocytosis and membrane receptor internalization: implication of F-BAR protein Carom. Front Biosci (Landmark Ed) 22:1439-1457
Yang, Ping; Wei, Xin; Zhang, Jian et al. (2016) Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells. Arterioscler Thromb Vasc Biol 36:361-9
Xi, Hang; Zhang, Yuling; Xu, Yanjie et al. (2016) Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells. Circ Res 118:1525-39
Li, Ya-Feng; Huang, Xiao; Li, Xinyuan et al. (2016) Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair. Front Biosci (Landmark Ed) 21:178-91
Li, Ya-Feng; Li, Rong-Shan; Samuel, Sonia B et al. (2016) Lysophospholipids and their G protein-coupled receptors in atherosclerosis. Front Biosci (Landmark Ed) 21:70-88
Ferrer, Lucas M; Monroy, Alexandra M; Lopez-Pastrana, Jahaira et al. (2016) Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J Cardiovasc Transl Res 9:135-44
Li, Xinyuan; Fang, Pu; Li, Yafeng et al. (2016) Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation. Arterioscler Thromb Vasc Biol 36:1090-100
Yin, Ying; Li, Xinyuan; Sha, Xiaojin et al. (2015) Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. Arterioscler Thromb Vasc Biol 35:804-16
Monroy, M Alexandra; Fang, Jianhua; Li, Shan et al. (2015) Chronic kidney disease alters vascular smooth muscle cell phenotype. Front Biosci (Landmark Ed) 20:784-95

Showing the most recent 10 out of 36 publications