The presence of two 15-lipoxygenases (15-LOXs), namely, 15-LOX1 and 15-LOX2, has been reported in humans. 15-LOX1 while preferentially metabolizes linoleic acid (LA) to 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE) also converts arachidonic acid (AA) to 15-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). On the other hand, 15-LOX2 specifically metabolizes AA to 15(S)-HETE. In regard to their tissue distribution, 15-LOX1 has been shown to be present in a wide variety of cell types including reticulocytes, macrophages and monocytes, whereas the expression of 15-LOX2 appears to be restricted to epithelial cell types in cornea, lung, prostate and skin. Although the presence of 15-LOX2 in the vessel wall has not been reported yet, vascular smooth muscle cells (VSMC) and endothelial cells (EC) express 15-LOX1 (also known as 12/15-LOX in murines) and when these cells are exposed to AA, they produce both 15(S)-HETE and 12(S)-HETE. Although, the involvement of 12(S)-HETE in vascular diseases has been fairly studied, relatively nothing is known about the role of 15(S)-HETE. In this aspect, the work in our laboratory pointed out that 15(S)-HETE is a potent stimulator of angiogenesis. Since angiogenesis plays a crucial role in vascular diseases, it is essential to investigate whether 15-LOX-15(S)-HETE axis, via inducing angiogenesis, influences vascular diseases. Towards achieving this goal, we propose to study the following five specific aims.
Specific Aim 1 : To determine the role of Egr-1 in 15(S)-HETE-induced human dermal micro vascular endothelial cell (HDMVEC) migration and tube formation and aortic ring and Matrigel plug angiogenesis.
Specific Aim 2 : 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require Egr-1-mediated induction of expression of fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF).
Specific Aim 3 : 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require 3-hydroxy-3-methyl glutaryl coenzyme-A reductase (HMGCR) activity.
Specific Aim 4 : 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require HMGCR-dependent expression and release of matrix metalloproteinases (MMP)-2 and -9.
Specific Aim 5 : Inhibition of 12/15-LOX reduces intraplaque angiogenesis and atherosclerotic lesions. The results of the experiments proposed in the above-listed five specific aims will provide novel information in terms of the role of 15-LOX-15(S)-HETE axis in vascular diseases and the potential new mechanisms by which this lipid molecule exerts such vascular wall remodeling.
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