Abstract 5540: Endothelial Intrinsic NF-κB Mediates Systemic Hypotension and Vascular Dysfunction in Marine Model of Endotoxemia
NF-κB activation plays a central role in the pathogenesis of septic shock. Vascular endothelium is a key regulator of vascular tone and vascular homeostasis. Endothelial intrinsic NF-κB activity may play a critical role in the pathophysiology of septic vascular dysfunction. The causal role of endothelial NF-κB activation in septic shock and septic vascular dysfunction has not been examined. This study defined the causative role endothelial intrinsic NF-κB in the development of systemic hypotension and vascular dysfunction in endotoxemic mice. Wild type (WT) and transgenic mice (TG) that conditionally overexpress a mutant I-κBα, a superior inhibitor of NF-κB, selectively on endothelium, were injected with saline (1 ml/kg, i.p.) or E Coli LPS (4–10 mg/kg, i.p.). Mean systemic blood pressure (MBP), vasoconstrictor response to norepinephrine (NE, 0.03, 0.1 and 0.3 μg/kg, i.v.), and vasodilator responses to endothelium-dependent and -independent vasodilator, acetylcholine (Ach, 0.06, 0.2 and 0.6 μg/kg, i.v.) and sodium nitroprusside (SNP, 0.06, 0.2 and 0.6 μg/kg, i.v.) were monitored. At 4 hours post-LPS, MBP for WT-con, TG-con, WT-LPS and TG-LPS groups was 76±7, 79±5, 37±4 and 62±6 mmHg, respectively (P < 0.05 between WT-LPS and TG-LPS groups). Increase in MBP caused by the 3 doses of NE was 30±2, 50±2 and 60±5 mmHg for WT-con, 27±3, 46±2 and 55±3 mmHg for TG-con, 14±1, 29±4 and 40±3 mmHg for WT-LPS and 29±1, 54±3 and 63±5 mmHg for TG-LPS groups (P < 0.05 between WT-LPS and TG-LPS groups at all doses). Both Ach and SNP caused a dose-dependent drop in MBP in WT-con and TG-con mice. The vasodilator response to Ach, but not to SNP was significantly blunted in WT-LPS mice. The impairment of vasodilator response to Ach was prevented in TG-LPS mice. Our results demonstrate that endothelial intrinsic NF-κB plays a pivotal in the pathogenesis of endotoxemic shock and vascular dysfunction.
Supported by NIH GM063907.