An excessive inflammatory reaction following injury to vessel wall is now believed to be the major factor in atherogenesis. Phospholipase A2s (PLA2s), a group of rate-limiting enzymes for production of arachidonic acid, play an important role in inflammation. Among the many types of PLA2s identified to date, evidence indicates for an involvement of both cytosolic and secretary type PLA2s (cPLA2 and sPLA2s) in inflammation. Activation of these PLA2s in dysfunctional endothelial cells, via production of arachidonic acid, the precursor for eicosanoids, can trigger a cascade of events, including induction of expression of cell adhesion molecules, that, in turn, may result in recruitment of immune cells (leukocytes and monocytes) to the site of vascular injury/infection as well as migration of vascular smooth muscle cells (VSMC) from media to intima. Transmigration of immune cells into sub-endothelial space and their activation also results in the production of a variety of molecules, including cytokines, eicosanoids, peptide growth factors and reactive oxygen species. Many of these molecules are both chemotactic and mitogenic to VSMC, and therefore, may provide a chain of cues for continued migration of these cells from media to intima and their multiplication in intima leading to neointima formation. In this aspect, our preliminary results, for the first time, reveal that Jak/STAT-dependent cPLA2 expression and arachidonic acid release are involved in VSMC migration induced by receptor tyrosine kinase (RTK) agonist, platelet-derived growth factor-BB (PDGF-BB). Based on this novel and exciting finding, we suspect an important role for cPLA2 in VSMC migration from media to intima in response to various bioactive molecules that are produced at the site vascular injury, and thereby, contribute to neointima formation. We will test this hypothesis by addressing the following three specific aims: 1. To study the role of cPLA2 in RTK and G protein-coupled receptor (GPCR) agonist-induced VSMC migration. 2. To study the role of the Jak-STAT pathway in RTK and GPCR agonist-induced cPLA2 expression, arachidonic acid release and VSMC migration. 3. To study the role of cPLA2 and the Jak/STAT pathway in VSMC migration, proliferation and neointima formation in models of rat and/or mouse vascular injury. The results of the above three specific aims will provide novel information in regard to the role of cPLA2 and Jak/STAT signaling in VSMC migration and neointima formation. Such knowledge will be useful in the development of potential therapeutics targeting inflammatory vascular diseases such as atherosclerosis and restenosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064165-08
Application #
7046063
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2000-02-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$285,138
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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

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