Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice

Background—Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice. Methods and Results—To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (±), or homozygous null (−/−) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1+/+ and HO-1+/− mice, whereas HO-1−/− mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1−/− mice (121±5 mm Hg) after 24 hours, compared with HO-1+/+ (96±7 mm Hg) and HO-1+/− (89±13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP respo...