Atherosclerosis (AS) is a leading cause of mortality in the U.S. The vasopressor peptide of the renin- angiotensin system, Ang II, is potently pro-atherogenic due to its ability to induce inflammation. Specifically, Ang II induces production of interleukin-6 (IL-6), a cytokine that activates adhesion molecule expression and monocyte recruitment locally, and the hepatic acute-phase response (APR) systemically. The latter phenomenon is responsible for increased circulating C-reactive protein (CRP), used as a biomarker of vascular inflammation. Intracellular IL-6 signaling activates the signal transducer and activator of transcription (STAT)-3. The major hypothesis of this proposal is that the Ang II-induced IL-6-Jak-STAT3 signaling pathway plays an important, early, role in plaque development through both local and systemic actions. Local vascular actions are to affect endothelial cell sensitivity to ROS, monocyte recruitment and vascular remodeling;systemic actions are to mediate expression of hepatic APRs. In the past funding period, we have defined novel molecular events in IL-6-Jak-STAT3 signaling and confirmed their relevance in vivo. We were the first to show IL-6 induced acetylation of the STAT3 NH2 terminus, and demonstrated its requirement in target gene expression;we have found that Ang II infusion activates a local Jak-STAT3 pathway in the LDLR-/- mouse. We propose to extend these studies in three aims: 1. Determine how STAT3 NH2 terminal acetylation mediates target gene expression. Coimmunoprecipitation assays, and confocal colocalization experiments will be used to identify domains of p300 that bind the NH2 terminus of STAT-3. The role of the STAT3 NH2 terminus in p300 recruitment and enhanceosome formation in native chromatin will be investigated using chromatin immunoprecipitation assays. 2. Determine the role of transcriptional elongation in STAT3- dependent target gene expression. Recently we found that IL-6 induces STAT3 association with CDK-9, a component of the RNA Pol II kinase, P-TEFb. We will examine whether phospho-Tyr and Ac-Lys-modified STAT3 bind P-TEFb the role of CDK-9 effect on RNA Pol II carboxy terminal domain phosphorylation and transcriptional elongation. 3. Identify the effect of activating the IL-6-Jak- STAT3 pathway in vivo. Ang II infusions in our double IL-6-/- - LDLR-/- knockout mice will be used to determine IL-6 dependence for monocyte recruitment, cytoprotection from ROS stress, induction of the hepatic APR, and effect on vascular remodeling focusing on its potential role in activating downstream plasminogen activator-1 and TGF?, pathways. Together, these studies will elucidate novel mechanisms for the IL-6-STAT3 signaling pathway and define their specific roles in vascular inflammation, atherosclerotic plaque formation, and vascular remodeling.

Public Health Relevance

Vascular inflammation is a major risk factor for atherosclerotic heart disease through unknown mechanisms. Production of inflammatory cytokines, such as IL-6, by the vessel wall has been associated with atherosclerosis and enhanced mortality. This project seeks to understand the role(s) of IL-6 plays in inflammation. This work will point to key regulatory steps that can be suppressed as a treatment for atherosclerosis and heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Charette, Marc F
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University of Texas Medical Br Galveston
Internal Medicine/Medicine
Schools of Medicine
United States
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Ju, Xiaoxi; Ijaz, Talha; Sun, Hong et al. (2014) IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome. J Am Heart Assoc 3:e000476
Ray, Sutapa; Zhao, Yingxin; Jamaluddin, Mohammad et al. (2014) Inducible STAT3 NH2 terminal mono-ubiquitination promotes BRD4 complex formation to regulate apoptosis. Cell Signal 26:1445-55
Ju, Xiaoxi; Ijaz, Talha; Sun, Hong et al. (2013) Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice. Arterioscler Thromb Vasc Biol 33:1612-21
Ray, Sutapa; Ju, Xiaoxi; Sun, Hong et al. (2013) The IL-6 trans-signaling-STAT3 pathway mediates ECM and cellular proliferation in fibroblasts from hypertrophic scar. J Invest Dermatol 133:1212-20
Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K et al. (2013) Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33:2172-9
Tieu, Brian C; Ju, Xiaoxi; Lee, Chang et al. (2011) Aortic adventitial fibroblasts participate in angiotensin-induced vascular wall inflammation and remodeling. J Vasc Res 48:261-72
Brasier, Allan R (2010) The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovasc Res 86:211-8
Ray, Sutapa; Lee, Chang; Hou, Tieying et al. (2010) Regulation of signal transducer and activator of transcription 3 enhanceosome formation by apurinic/apyrimidinic endonuclease 1 in hepatic acute phase response. Mol Endocrinol 24:391-401
Tieu, Brian C; Lee, Chang; Sun, Hong et al. (2009) An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 119:3637-51
Hou, Tieying; Ray, Sutapa; Lee, Chang et al. (2008) The STAT3 NH2-terminal domain stabilizes enhanceosome assembly by interacting with the p300 bromodomain. J Biol Chem 283:30725-34

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