Title: LysoPI/GPR55 pathway promotes endothelial activation, vascular inflammation and
atherosclerosis
Atherosclerosis and its complications are the leading cause of morbidity and mortality in the US. Novel
antiinflammatory therapies are urgently needed to inhibit atherosclerosis. The goal of this project is to
determine the roles and mechanisms underlying lysophosphatidylinositol (lysoPI) promoted endothelial
cell (EC) activation and atherosclerosis. We published numerous papers on EC activation,
atherosclerosis and lysophospholipids (lysolipids). Our strong preliminary data and publications
show that: 1) we reported a new concept that most lysolipids are new conditional classical damage-
associated molecular pattern (DAMPs) that do not bind to classical DAMP receptors but bind to their
own receptors to stimulate inflammation; 2) our metabolomics data showed that lysoPI is significantly
increased in the aortas and plasma of ApoE-/- mice fed with high fat diet (HF) for three weeks; 3) lysoPI
specifically bind to its receptor, G protein coupled receptor 55 (GPR55), and activates primary human
aortic endothelial cells (HAECs) by upregulating EC adhesion molecule ICAM-1; 4) Mechanistically,
lysoPI induces generation of mitochondrial reactive oxygen species (mtROS) in HAECs and induces
proinflammatory proteinarginine methyltransferase 1(PRMT1) activity; 5) our RNA-Seq data showed
that significantly different from that induced by lysoPI's relative lysoPC, lysoPI induces sustained EC
activation by upregulating DAMP receptors inflammasomes/caspase-1 and proinflammatory
secretomes; 6) we established ApoE-/-/GPR55-/- DKO mice; and DKO mice have significantly
decreased atherosclerosis in comparison to that in ApoE KO mice fed with HF for 12 weeks; and finally,
7) we generated EC-specific GPR55 KO mice and PRMT1 KO mice. Based on our strong preliminary
data and publications, the central
hypothesis
to be tested is that early hyperlipidemia-induced lysoPI
stimulates and sustains aortic EC activation via a GPR55-PRMT1 pathway, proinflammatory monocyte
(MC) recruitment, thereby contributing to atherosclerosis. We will test this hypothesis using three aims.
Aim 1 will determine expression and function of lysoPI/GPR55-PRMT1 pathway in HAECs activated by
hyperlipidemic stimuli and in aortas of ApoE-/- mice (relevant studies). Aim 2 will examine the
mechanisms by which lysoPI/GPR55 induces sustained aortic EC activation via inducing PRMT1
upregulation-mtROS generation, which further prolongs EC activation (mechanistic studies). Aim 3 will
determine whether inhibition of lysoPI/GPR55 and PRMT1 in EC (EC-specific KO) and other vascular
cells (global KO) would decrease atherogenesis in ApoE-/- mice (therapeutic studies).