Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe -/- mice

被引:53
作者
Di Marco, E. [1 ,2 ]
Gray, S. P. [1 ]
Chew, P. [1 ]
Koulis, C. [1 ]
Ziegler, A. [3 ]
Szyndralewiez, C. [4 ]
Touyz, R. M. [5 ,6 ]
Schmidt, H. H. H. W. [7 ,8 ]
Cooper, M. E. [1 ]
Slattery, R. [3 ]
Jandeleit-Dahm, K. A. [1 ,2 ]
机构
[1] Baker IDI Heart & Diabet Inst, Diabet Complicat Div, Melbourne, Vic 8008, Australia
[2] Monash Univ, Dept Med, Melbourne, Vic 3004, Australia
[3] Monash Univ, Dept Immunol, Melbourne, Vic 3004, Australia
[4] Genkyotex SA, Geneva, Switzerland
[5] Ottawa Hosp, Res Inst, Ottawa, ON, Canada
[6] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland
[7] Maastricht Univ, Fac Med Hlth & Life Sci, Dept Pharmacol, Maastricht, Netherlands
[8] Maastricht Univ, Fac Med Hlth & Life Sci, Cardiovasc Res Inst Maastricht CARIM, Maastricht, Netherlands
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
Atherosclerosis; Diabetes; Immune system; Inflammation; NOX; OXIDATIVE STRESS; ACCELERATED ATHEROSCLEROSIS; NADPH OXIDASE; CARDIOVASCULAR-DISEASE; SUPEROXIDE-PRODUCTION; DEFICIENT MICE; T-LYMPHOCYTES; HIGH GLUCOSE; EXPRESSION; CELLS;
D O I
10.1007/s00125-013-3118-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis. Diabetes was induced in male Apoe (-/-) mice with five daily doses of streptozotocin (55 mg kg(-1) day(-1)). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe (-/-) mice for 10 weeks. Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c(+) cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe (-/-) mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFN gamma. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area. Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe (-/-) mice.
引用
收藏
页码:633 / 642
页数:10
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