A pivotal role of endothelial-specific NF-kappaB signaling in the pathogenesis of septic shock and septic vascular dysfunction.
Although the role of NF-kappaB in the pathogenesis of sepsis and septic shock has been extensively studied, little is known about the causative contribution of endothelial-intrinsic NF-kappaB to these pathological processes. In this study, we used transgenic (TG) mice (on FVB genetic background) that conditionally overexpress the NF-kappaB inhibitor, mutant I-kappaBalpha, selectively on endothelium and their transgene-negative littermates (wild type (WT)) to define the causative role of endothelial-specific NF-kappaB signaling in septic shock and septic vascular dysfunction. In WT mice, LPS challenge caused systemic hypotension, a significantly blunted vasoconstrictor response to norepinephrine, and an impaired endothelium-dependent vasodilator response to acetylcholine, concomitant with a markedly increased aortic inducible NO synthase expression, significantly elevated plasma and aortic levels of nitrite/nitrate, increased aortic TNF-alpha expression, and decreased aortic endothelial NO synthase (eNOS) expression. In TG mice whose endothelial NF-kappaB was selectively blocked, LPS caused significantly less hypotension and no impairments in vasoconstrictor and endothelium-dependent vasodilator responses, associated with significantly reduced aortic inducible NO synthase expression, decreased plasma and aortic levels of nitrite/nitrate, reduced aortic TNF-alpha expression, and increased aortic eNOS expression. TNF-alpha knockout mice prevented LPS-induced eNOS down-regulation. WT mice subjected to cecal ligation and puncture showed significant systemic hypotension, which was prevented in TG mice. Our data show that selective blockade of endothelial-intrinsic NF-kappaB pathway is sufficient to abrogate the cascades of molecular events that lead to septic shock and septic vascular dysfunction, demonstrating a pivotal role of endothelial-specific NF-kappaB signaling in the pathogenesis of septic shock and septic vascular dysfunction.
Ding
Jianqiang
J
Division of Pulmonary and Critical Care Medicine, Centers for Heart and Lung Research, and Immunology and Inflammation, Feinstein Institute for Medical Research, New Hyde Park, NY 11040, USA.
Song
Dongmei
D
Ye
Xiaobing
X
Liu
Shu Fang
SF
D000818:Animals; D004727:Endothelium / Q000378:metabolism*; D015870:Gene Expression; D006439:Hemodynamics / Q000187:drug effects; D020672:I-kappa B Proteins / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D012772:Shock, Septic / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014652:Vascular Diseases / Q000209:etiology*
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase
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