Inflammation, in excess, was believed to be an underlying factor in the pathogenesis of proliferative cardiovascular diseases such as atherosclerosis. Phospholipase A2s (PLA2s) play an important role in inflammation. Arachidonic acid (AA), which is produced primarily by PLA2s, metabolizes via the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 monooxygenase (CYP) pathways producing prostaglandins (PGs), hydroperoxyeicosatetraenoic acids (HPETEs) and epoxyeicosatrienoic acids (EETs), respectively. While some of the COX and LOX products of AA are pro-inflammatory, CYP, particularly CYP2C8/9 products of AA, are anti-inflammatory. Atherosclerotic arteries produce 15(S)-HETE as a major 15- LOX product of AA. Although the involvement of 15-LOX1 in the oxidation of low-density lipoprotein has been extensively studied in understanding its role in the pathobiology of atherosclerosis, very little is known in regard to its AA product, 15(S)-HETE, in atherosclerosis. In this regard, during the previous funding cycle of this grant application, we have shown that 15(S)-HETE via inducing the expression of monocyte chemotactic protein-1 and interleukin-6 stimulates the migration of vascular smooth muscle cells, an important factor in vascular wall diseases. During the course of these studies, we also discovered that 15(S)-HETE stimulates macrophage migration. In addition, we observed that it activates Pyk2 and Syk, two non-receptor tyrosine kinases, and induces the expression of tissue factor, a clotting factor, and all of these molecules are involved in the mediation of inflammation. Based on these novel observations, we predict that eicosanoids, particularly the 15- LOX1/2 product of AA, 15(S)-HETE, via its capacity to trigger the migration and adhesion of macrophages to the aorta/artery under the influence of cardiovascular risk factors may set the soil for the development of atherosclerosis. To address this hypothesis, we have proposed to test the following specific aims:
Aim 1 : 15- LOX-15(S)-HETE via activating Pyk2 and Syk, two non-receptor tyrosine kinases, plays a key role in the stimulation of THP1 cell migration.
Aim 2 : 15-LOX-15(S)-HETE-induced THP1 cell migration requires TF expression and secretion.
Aim 3 : 12/15-LOX activity is required for stimulus-induced vascular inflammation. Thus, the experiments proposed in this grant application will provide novel information in regard to the potential role of 15-LOX-15(S)-HETE axis in macrophage recruitment and its adhesion to the aorta/artery leading to inflammation and development of atherosclerosis. Such knowledge would be useful in the development of therapeutic drugs against vascular diseases such as atherosclerosis.
Inflammation and endothelial cell (EC) dysfunction are crucial factors in the development of atherosclerosis. Although, atherosclerotic arteries have been shown to produce 15(S)-HETE as a major eicosanoid, its role in vascular wall remodeling is less clear. In this regard, the present grant proposal seeks to study the molecular mechanisms by which 15(S)-HETE mediates inflammation and thereby sets the soil for the initiation of EC dysfunction and atherosclerosis.
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