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.
|Singh, Nikhlesh K; Rao, Gadiparthi N (2018) Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res 73:28-45|
|Kotla, Sivareddy; Singh, Nikhlesh K; Rao, Gadiparthi N (2017) ROS via BTK-p300-STAT1-PPAR? signaling activation mediates cholesterol crystals-induced CD36 expression and foam cell formation. Redox Biol 11:350-364|
|Singh, Nikhlesh K; Janjanam, Jagadeesh; Rao, Gadiparthi N (2017) p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine-induced vascular smooth muscle cell migration and proliferation. J Biol Chem 292:14080-14091|
|Kotla, Sivareddy; Singh, Nikhlesh K; Kirchhofer, Daniel et al. (2017) Heterodimers of the transcriptional factors NFATc3 and FosB mediate tissue factor expression for 15(S)-hydroxyeicosatetraenoic acid-induced monocyte trafficking. J Biol Chem 292:14885-14901|
|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|
|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; Wang, Dong; Kundumani-Sridharan, Venkatesh et al. (2011) 15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeli J Biol Chem 286:22478-88|
|Wang, Dong; Paria, Biman C; Zhang, Qiuhua et al. (2009) A role for Gab1/SHP2 in thrombin activation of PAK1: gene transfer of kinase-dead PAK1 inhibits injury-induced restenosis. Circ Res 104:1066-75|
|Potula, Harihara S K; Wang, Dong; Quyen, Dong Van et al. (2009) Src-dependent STAT-3-mediated expression of monocyte chemoattractant protein-1 is required for 15(S)-hydroxyeicosatetraenoic acid-induced vascular smooth muscle cell migration. J Biol Chem 284:31142-55|
Showing the most recent 10 out of 23 publications