Inflammation, in excess, was believed to be an underlying factor in the pathogenesis of proliferative cardiovascular diseases such as atherosclerosis and restenosis following angioplasty. Nuclear factors of activated T cells (NFATs) are members of a multigene family of transcriptional factors that relate to Rel group and play an important role in the regulation of immune responses and inflammation. Apart from the above-cited functions, during the previous funding cycles of this grant, the work in our laboratory showed that 1. Activation of calcineurin-NFAT signaling is required for both receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) agonist-induced vascular smooth muscle cell (VSMC) growth and motility;2. Blockade of calcineurin-NFAT activation signaling inhibits balloon injury-induced neointima formation in a rat carotid artery model;and 3. Cyclins such as cyclin D1 and cyclin A2 and proinflammatory cytokines such as IL-6 appear to be the NFAT-target genes in mediating RTK and GPCR agonist-induced VSMC growth and motility and injury- induced vascular wall remodeling. Towards understanding the unifying role of NFATs in vascular wall remodeling in response to various cues, we have recently discovered that monocyte chemoattractant protein-1 (MCP-1), a potent chemokine that appears to play an important role in vascular diseases, possesses the capacity to activate NFATs in human aortic smooth muscle cells (HASMCs). Indeed, our preliminary results indicate that MCP-1 activates NFATc1 and it is required for MCP-1-induced HASMC growth and motility. These novel observations led us to hypothesize that NFATs are the major mediators of vascular wall remodeling and thereby they could become potential targets for drug development against these vascular diseases. To test this hypothesis, we will address the following three specific aims: 1. NFATc1 mediates MCP- 1-inducd HASMC growth and motility;2. MCP-1-induced HASMC growth and motility require NFATc1-cyclin D1-dependent activation of protein kinase C-related kinase 1 (PRK1) and p21-activated kinase 1 (PAK1) and 3. Smooth muscle (SM)-NFATc1 mediates vascular wall remodeling. Given the capacity of MCP-1 in the propagation of inflammation, the results of the proposed experiments in these specific aims will provide us new information to our understanding of whether NFATc1 plays a unifying role in the pathogenesis of vascular diseases such as restenosis and such knowledge eventually may pave a way to develop new and better therapeutic drugs against these vascular diseases.
Vascular smooth muscle cell (VSMC) migration and proliferation play an important role in peripheral vascular diseases such as atherosclerosis and restenosis following angioplasty or vein grafting. Elucidating the molecular mechanisms underlying VSMC migration and proliferation is crucial in the development of therapeutic agents to control the disease process of these vascular lesions. In this regard, the present grant proposal seeks to study the mechanisms by which NFATc1, a member of the nuclear factors of activated T cells family of transcriptional factors, plays a unifying role in mediating VSMC proliferation and migration in response to various cues and ignite the disease process.
|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|
|Karpurapu, Manjula; Wang, Dong; Van Quyen, Dong et al. (2010) Cyclin D1 is a bona fide target gene of NFATc1 and is sufficient in the mediation of injury-induced vascular wall remodeling. J Biol Chem 285:3510-23|
|Karpurapu, Manjula; Wang, Dong; Singh, Nikhlesh K et al. (2008) NFATc1 targets cyclin A in the regulation of vascular smooth muscle cell multiplication during restenosis. J Biol Chem 283:26577-90|
|Wang, Dong; Liu, Zhimin; Li, Quanyi et al. (2007) An essential role for gp130 in neointima formation following arterial injury. Circ Res 100:807-16|
|Dronadula, Nagadhara; Rizvi, Farhan; Blaskova, Eva et al. (2006) Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility. J Lipid Res 47:767-77|
|Liu, Zhimin; Zhang, Chunxiang; Dronadula, Nagadhara et al. (2005) Blockade of nuclear factor of activated T cells activation signaling suppresses balloon injury-induced neointima formation in a rat carotid artery model. J Biol Chem 280:14700-8|
|Dronadula, Nagadhara; Liu, Zhimin; Wang, Chunmei et al. (2005) STAT-3-dependent cytosolic phospholipase A2 expression is required for thrombin-induced vascular smooth muscle cell motility. J Biol Chem 280:3112-20|
|Yellaturu, Chandrahasa R; Ghosh, Salil K; Rao, R K et al. (2002) A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation. Biochem J 368:183-90|