: Vascular smooth muscle cell (VSMC) migration from media to intima and its replication in intima is one of the underlying factors in the pathophysiology of atherosclerosis and restenosis. Several biogenic molecules such as peptide growth factors, cytokines, eicosanoids and oxidants that are generated at the site of arterial injury can trigger the formation of these vascular lesions via stimulating VSMC migration and proliferation. Therefore, elucidating the signal transduction mechanisms that are integral to VSMC migration and proliferation and shared by many of these biogenic molecules may lead to the development of therapeutic agents against these vascular lesions. The preliminary research in our laboratories showed that transcriptional factors namely nuclear factors of activated T cells (NFATs) are present in VSMC. Furthermore, platelet-derived growth factor-BB (PDGFBB) and thrombin, potent VSMC mitogens and chemokines activated NFATs in VSMC. More importantly, cyclosporin A, a potent and specific inhibitor of the NFAT activation pathway, significantly reduced PDGFBB and thrombin-induced DNA synthesis in VSMC. In view of these exciting findings we hypothesize that NFATs play an important role in agonist-induced VSMC migration and proliferation in vitro and injury-induced neointima formation in vivo. To achieve this goal we will propose to address the following four specific aims: 1) To determine the role of NFATs in receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonist-induced VSMC gene expression; 2) To determine the role of NFATs in RTK and GPCR agonist-induced VSMC growth; 3) To study the role of NFATs in VSMC migration in response to RTK and GPCR agonists; and 4) To study the role of NFATs in VSMC growth induction in rat carotid balloon injury model of restenosis. The results of the experiments proposed in this research project will provide novel information with regard to the role of NFATs in the regulation of RTK and GPCR agonist-induced VSMC growth and migration in vitro and in the pathogenesis of injury-induced restenosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069908-02
Application #
6622929
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2002-04-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-28
Support Year
2
Fiscal Year
2003
Total Cost
$286,000
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
Janjanam, Jagadeesh; Zhang, Baolin; Mani, Arul M et al. (2018) LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis. J Biol Chem 293:3088-3103
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
Janjanam, Jagadeesh; Rao, Gadiparthi N (2016) Novel role of cortactin in G protein-coupled receptor agonist-induced nuclear export and degradation of p21Cip1. Sci Rep 6:28687
Singh, Nikhlesh K; Kotla, Sivareddy; Dyukova, Elena et al. (2015) Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice. Nat Commun 6:7450
Janjanam, Jagadeesh; Chandaka, Giri Kumar; Kotla, Sivareddy et al. (2015) PLC?3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration. Mol Biol Cell 26:4589-606
Gadepalli, Ravisekhar; Kotla, Sivareddy; Heckle, Mark R et al. (2013) Novel role for p21-activated kinase 2 in thrombin-induced monocyte migration. J Biol Chem 288:30815-31
Kundumani-Sridharan, Venkatesh; Singh, Nikhlesh K; Kumar, Sanjay et al. (2013) Nuclear factor of activated T cells c1 mediates p21-activated kinase 1 activation in the modulation of chemokine-induced human aortic smooth muscle cell F-actin stress fiber formation, migration, and proliferation and injury-induced vascular wall remodeli J Biol Chem 288:22150-62
Keilani, Serene; Chandwani, Samira; Dolios, Georgia et al. (2012) Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element. J Neurosci 32:6808-18
Singh, Nikhlesh K; Kundumani-Sridharan, Venkatesh; Kumar, Sanjay et al. (2012) Protein kinase N1 is a novel substrate of NFATc1-mediated cyclin D1-CDK6 activity and modulates vascular smooth muscle cell division and migration leading to inward blood vessel wall remodeling. J Biol Chem 287:36291-304
Gadepalli, Ravisekhar; Singh, Nikhlesh K; Kundumani-Sridharan, Venkatesh et al. (2012) Novel role of proline-rich nonreceptor tyrosine kinase 2 in vascular wall remodeling after balloon injury. Arterioscler Thromb Vasc Biol 32:2652-61

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