Extensive evidence indicates that complement (C), in particular the C membrane attack complex (C/MAC), a key mediator of inflammation and immunity, plays a critical role in atherogenesis. However, mechanisms underlying C/MAC-accelerated atherogenesis is unknown. Recent trails of C-targeted therapeutics to inhibit C/MAC formation presented some benefit to reduce mortality in patients undergoing coronary artery bypass grafting but lack of consist benefit for myocardial infarction. Research to further understand mechanisms underlying C/MAC-accelerated atherogenesis is in great needs and would lead to the development of better therapeutic strategies for cardiovascular disease. We recently discovered that the deficiency of a key C/MAC regulator CD59 (mCd59-/-) induced monocytes (MC, CD11b+), inflammatory MC subset (CD11b+/Ly6C+) and caspase-1 (Casp1) activation in MC. We also demonstrated that Casp-1 activation plays an essential role in sensing metabolic danger signal-associated molecular patterns (DAMPs) and in initiating vascular inflammatory. These results link C/MAC formation with inflammatory MC differentiation, Casp1 activation and inflammasome activation in MC, which may contribute to vascular inflammation and atherogenesis. The effect of C/MAC on inflammatory MC differentiation and Casp-1 activation and its role in atherogenesis have not been studied before. In this project, we proposed four connected aims to investigate 1) the effect of C/MAC on MC expansion and differentiation, and atherosclerosis; 2) the molecular mechanism underlying C/MAC-induced Ly6C+ inflammatory MC differentiation; 3) the role of Casp-1 in C/MAC-induced Ly6C+ inflammatory MC differentiation and atherosclerosis; and 4) the therapeutic effect of C/MAC or Casp-1 inhibitors on C/MAC-induced MC differentiation and atherosclerosis. This study would provide important insights into our understanding about the role of complement system in atherosclerosis and inflammation, will open a new avenue to prevent and treat atherosclerosis, and will foster the development of new therapeutic strategies for cardiovascular disease.

Public Health Relevance

- In this application, we will investigate the role and underlying mechanism of complement (C) system, in particular the C membrane attack complex (MAC), a key mediator of inflammation and immunity, in promoting inflammasome activation, monocyte differentiation and atherosclerosis. We will test whether the inhibition of MAC and/or MAC-induced inflammasome activation could prevent atherogenesis. This study would provide important insights into our understanding about the role of complement system in atherosclerosis and inflammation, will open a new avenue to prevent and treat atherosclerosis, and will foster the development of new therapeutic strategies for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130233-04
Application #
9691988
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hasan, Ahmed a K
Project Start
2016-07-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Cueto, Ramon; Zhang, Lixiao; Shan, Hui Min et al. (2018) Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment. Redox Biol 17:70-88
Cheng, Zhongjian; Shen, Xinggui; Jiang, Xiaohua et al. (2018) Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. Redox Biol 16:215-225
Xu, Keman; Yang, William Y; Nanayakkara, Gayani Kanchana et al. (2018) GATA3, HDAC6, and BCL6 Regulate FOXP3+ Treg Plasticity and Determine Treg Conversion into Either Novel Antigen-Presenting Cell-Like Treg or Th1-Treg. Front Immunol 9:45
Fang, Pu; Li, Xinyuan; Dai, Jin et al. (2018) Immune cell subset differentiation and tissue inflammation. J Hematol Oncol 11:97
Sun, Yu; Johnson, Candice; Zhou, Jun et al. (2018) Uremic toxins are conditional danger- or homeostasis-associated molecular patterns. Front Biosci (Landmark Ed) 23:348-387
Li, Xinyuan; Wang, Luqiao; Fang, Pu et al. (2018) Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation. J Biol Chem 293:11033-11045
Li, Xinyuan; Shao, Ying; Sha, Xiaojin et al. (2018) IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14). Arterioscler Thromb Vasc Biol 38:599-609
Liu, Fengming; Sahoo, Rupam; Ge, Xiaowen et al. (2017) Deficiency of the complement regulatory protein CD59 accelerates the development of diabetes-induced atherosclerosis in mice. J Diabetes Complications 31:311-317
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
Shao, Ying; Nanayakkara, Gayani; Cheng, Jiali et al. (2017) Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury. Antioxid Redox Signal :

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