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.