Vascular inflammation, insulin resistance, and endothelial dysfunction in salt-sensitive hypertension: role of nuclear factor kappa B activation.
OBJECTIVE
Activation of the nuclear factor kappa B (NF kappaB) 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 kappaB 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 kappaB 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 (O2) production (148%), and expression of monocyte chemoattractant protein-1, tumor necrosis factor alpha, phospho-I kappaB alpha, and phospho-(Ser536)-p65NF kappaB. Pyrrolidine dithiocarbamat significantly improved endothelium-dependent relaxation, reduced vascular O2, 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.


CONCLUSIONS
The current findings strongly suggest that activation of the NF kappaB 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.
Zhou
Ming-Sheng
MS
Nephrology-Hypertension Section, Veterans Affairs Medical Center and Division of Nephrology and Hypertension and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida 33125, USA. mzhou2@med.miami.edu
Schulman
Ivonne Hernandez
IH
Raij
Leopoldo
L
D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002097:C-Reactive Protein / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism* / Q000503:physiopathology
D018932:Chemokine CCL2; D007328:Insulin; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D012965:Sodium Chloride; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt