: Atherosclerosis (AS) is a chronic inflammatory disease that remains a leading killer in Western Countries. A wealth of research has shown that vascular production of interleukin-6 (IL-6) and its biological effect of enhancing hepatic acute phase reactant production (such as C-reactive protein) is strongly related to atherosclerotic lesion development in humans. Similarly, activity of the renin-angiotensin system (RAS) is linked to acceleration of LDL-induced AS, as inhibitors of the RAS reduce atherosclerotic lesions in experimental animals, and reduce ischemic cardiovascular events in humans. We have recently discovered the mechanism for a feedback loop between IL-6 mediated chronic inflammation and the RAS, which may provide a unifying mechanism that relating vascular inflammation, IL-6 secretion, RAS activity and atherogenesis. For example, we have shown that AII is a proinflammatory agent in vascular smooth muscle cells, inducing IL-6 expression; IL-6, in turn, enhances expression of the AII precursor, angiotensinogen (AGT), in the liver by activating the signal transducer and activator of transcription (STAT3) molecules. In this project, we propose the hypothesis that lipid-induced vascular inflammation initiates a biological positive feedback loop which amplifies pro-atherogenic RAS activity and enhances atherogenesis. We propose four specific aims to test the molecular mechanisms in IL-6 inducible RAS expression and AS.
Aim 1 will examine the role of acetylation! deacylation in IL-6 inducible STAT3 activity and identify its mechanism.
Aim 2 will examine the relationships between vascular inflammation, the hepatic acute phase response and changes in RAS activity in genetically-susceptible LDL receptor deficient (LDLR-/-) mice challenged with a high fat (Western) diet.
Aim 3 will determine the contribution of endogenous modulation of the RAS on vascular inflammation and atherogenesis in the LDLR-/- mouse.
Aim 4 will determine the requirement for IL-6 atherogenesis by examining the atherogenic phenotype of LDLR-/- mice deficient in JL-6 secretion and ask whether IL-6 expression is required for RAS activation. These studies will determine new targets for anti-inflammatory therapy in high-risk patients for AS.
|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. (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; 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|
|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|
|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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