期刊
JOURNAL OF HYPERTENSION
卷 28, 期 3, 页码 527-535出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e3283340da8
关键词
endothelial dysfunction; hypertension; insulin resistance; nuclear factor kappa B; vascular injury
资金
- American Heart Association Scientist Development Award
- University of Miami SAC Research Grant
- South Florida Veterans Affairs Foundation for Research and Education
Objectives Activation of the nuclear factor kappa B (NF kappa B) inflammatory pathway by angiotensin II and reactive oxygen species may play an important role in the development of insulin resistance and cardiovascular injury in hypertensive and metabolic diseases. We have shown that in hypertensive Dahl salt-sensitive rats, upregulation of angiotensin II and reactive oxygen species contributed to increased vascular inflammatory gene expression, endothelial dysfunction, and insulin resistance. Herein, we investigated whether activation of NF kappa B contributes to the development of endothelial dysfunction, vascular injury, and vascular and peripheral insulin resistance in salt-sensitive hypertension. Methods Dahl salt-sensitive rats were fed a normal (0.5% NaCl) or high-salt diet (4% NaCl), or high-salt diet and pyrrolidine dithiocarbamat (150 mg/kg in drinking water), an inhibitor of NF kappa B activation, for 6 weeks. Results Hypertensive Dahl salt-sensitive rats manifested impaired endothelium-dependent relaxation to acetylcholine, aortic hypertrophy (35%), increased plasma C-reactive protein (25%), vascular superoxide (O-2(-)) production (148%), and expression of monocyte chemoattractant protein-1, tumor necrosis factor alpha, phospho-I kappa B alpha, and phospho-(Ser536)-p65NF kappa B. Pyrrolidine dithiocarbamat significantly improved endothelium-dependent relaxation, reduced vascular O-2(-), and normalized aortic hypertrophy and systemic and local inflammation, despite only mildly reducing blood pressure. Hypertensive Dahl salt-sensitive rats also manifested impaired insulin-mediated vasorelaxation and Akt/endothelial nitric oxide synthase phosphorylation and decreased insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate, -32%). Pyrrolidine dithiocarbamat significantly improved insulin-mediated vascular relaxation and Akt/endothelial nitric oxide synthase phosphorylation as well as insulin sensitivity. Conclusion The current findings strongly suggest that activation of the NF kappa B inflammatory pathway by angiotensin II-induced reactive oxygen species generation may importantly contribute to vascular injury, systemic inflammation, as well as vascular and peripheral insulin resistance in salt-sensitive hypertension. J Hypertens 28:527-535 (c) 2010 Wolters Kluwer Health (c) Lippincott Williams & Wilkins.
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