Inflammation is a key factor in the pathogenesis of various diseases including atherosclerosis. Disruption of the endothelial barrier function has been considered as one of the initiating factors in inflammation. Therefore, discovery of molecules that promote the resolution of inflammation may bear translational importance in the control of atherosclerosis. In this context, in recent years, ?-3 fatty acid-derived lipid molecules, Resolvins D and E (RvD/E) series, have attracted special attention due to their ability in the resolution of inflammation. However, despite their efficacy to resolute inflammation, very little is known about their capacities in atheroprotection. Previously, we have reported that 12/15-lipoxyegenase (12/15-LOX)-derived arachidonic acid product, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), via producing reactive oxygen species (ROS), disrupting endothelial cell (EC) barrier function, promoting leukocyte infiltration and inducing proinflammatory cytokine expression enhances atherogenesis. Since RvD/E are generated by sequential oxygenation of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) by 15-LOX and 5-LOX, we asked the question whether these molecules have any atheroptrotective effects, and if so, what are the underlying mechanisms? Toward this end, like RvE1, we observed that RvD1 also exerts atheroprotection. In addition, we have noted that this lipid mediator by restoring protein tyrosine phosphatase (PTP) SHP2 activity from inhibition by reactive oxygen species (ROS) protects adherens junction (AJ)/tight junction (TJ) integrity and EC barrier function. Based on these novel findings, we hypothesize that RvD1 via blocking ROS production and restoring PTP activity suppresses AJ/TJ protein tyrosine phosphorylation, maintains AJ/TJ integrity and EC barrier function, and thereby protects from inflammation and atherogenesis. To test this central hypothesis, we will address the following four specific aims.
Aim 1 : RvD1 protects EC barrier function from disruption by atherogenic stimuli via inhibition of Frk activation and AJ/TJ protein tyrosine phosphorylation and thereby promoting AJ/TJ integrity.
Aim 2 : RvD1 prevents AJ/TJ disruption by inhibition of ROS production and restoring SHP2 activity.
Aim 3 : RvD1 prevents EC-leukocyte and EC-monocyte interactions via restoring SHP2 and PP2A activities from inhibition by ROS leading to blockade of NF?B-mediated expression of cell adhesion molecules.
Aim 4 : RvD1 confers protection against diet-induced atherogenesis via inhibition of ROS production and restoring SHP2 and PP2A activities leading to prevention of EC AJ/TJ disruption and EC-leukocyte and EC-monocyte interactions. The results of this proposal will provide novel information on the mechanisms underlying the atheroprotective effects of RvD1.

Public Health Relevance

Endothelial dysfunction is a critical factor in the propagation of inflammation, which is an underlying event in the pathogenesis of atherosclerosis. Resolvin D1 possesses anti-inflammatory properties, but its role in atheroprotection is not completely understood. Toward this end, the experiments proposed in this grant application will address whether Resolvin D1 exerts atheroprotective effects and the underlying mechanisms by which this inflammation-resolution lipid molecule attenuates atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074860-14
Application #
9446970
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Srinivas, Pothur R
Project Start
2004-04-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
Chattopadhyay, Rima; Raghavan, Somasundaram; Rao, Gadiparthi N (2017) Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function. Redox Biol 12:438-455
Chattopadhyay, Rima; Tinnikov, Alexander; Dyukova, Elena et al. (2015) 12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction. J Lipid Res 56:562-77
Kotla, Sivareddy; Rao, Gadiparthi N (2015) Reactive Oxygen Species (ROS) Mediate p300-dependent STAT1 Protein Interaction with Peroxisome Proliferator-activated Receptor (PPAR)-? in CD36 Protein Expression and Foam Cell Formation. J Biol Chem 290:30306-20
Kotla, Sivareddy; Singh, Nikhlesh K; Traylor Jr, James G et al. (2014) ROS-dependent Syk and Pyk2-mediated STAT1 activation is required for 15(S)-hydroxyeicosatetraenoic acid-induced CD36 expression and foam cell formation. Free Radic Biol Med 76:147-62
Chattopadhyay, Rima; Dyukova, Elena; Singh, Nikhlesh K et al. (2014) Vascular endothelial tight junctions and barrier function are disrupted by 15(S)-hydroxyeicosatetraenoic acid partly via protein kinase C ?-mediated zona occludens-1 phosphorylation at threonine 770/772. J Biol Chem 289:3148-63
Kundumani-Sridharan, Venkatesh; Dyukova, Elena; Hansen 3rd, Dale E et al. (2013) 12/15-Lipoxygenase mediates high-fat diet-induced endothelial tight junction disruption and monocyte transmigration: a new role for 15(S)-hydroxyeicosatetraenoic acid in endothelial cell dysfunction. J Biol Chem 288:15830-42
Kotla, Sivareddy; Singh, Nikhlesh K; Heckle, Mark R et al. (2013) The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. Sci Signal 6:ra83
Singh, Nikhlesh K; Kundumani-Sridharan, Venkatesh; Rao, Gadiparthi N (2011) 12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation. Blood 118:5701-12
Kundumani-Sridharan, Venkatesh; Niu, Jixiao; Wang, Dong et al. (2010) 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression. Blood 115:2105-16
Singh, Nikhlesh K; Quyen, Dong Van; Kundumani-Sridharan, Venkatesh et al. (2010) AP-1 (Fra-1/c-Jun)-mediated induction of expression of matrix metalloproteinase-2 is required for 15S-hydroxyeicosatetraenoic acid-induced angiogenesis. J Biol Chem 285:16830-43

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