Ferritin is a cytoprotective antioxidant strategy of the endothelium. Phagocyte-mediated oxidant damage to vascular endothelium is involved in various vasculopathies, including atherosclerosis and pulmonary leak syndromes. Heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells, increasing cytotoxicity from oxidants. However, brief heme exposure followed by prolonged incubation induces heme oxygenase and ferritin, which protect endothelial cells from oxidant injury. Ferritin, which stores iron and has ferroxidase activity, is the primary cytoprotectant. A site-directed mutant of ferritin lacking ferroxidase activity is ineffective. Endothelial cells exposed to heme induce ferritin synthesis, which protects against oxidant damage. Ferritin's protective effect is dose-dependent and involves iron sequestration. Apoferritin, when added to endothelial cells, is taken up and protects against oxidant-mediated cytolysis. Studies show that ferritin, not heme oxygenase, is the main cytoprotectant. Ferritin's ferroxidase activity and iron sequestration capacity are critical for its protective role. The study demonstrates that endothelial cells can be protected from oxidant damage through ferritin, an intracellular iron sequestrant. The findings suggest that ferritin plays a critical role in antioxidant defense by sequestering iron and preventing oxidative damage. The study also highlights the importance of ferritin in protecting endothelial cells from heme-induced oxidative stress. The results indicate that ferritin is a key factor in the endothelium's defense against oxidant damage.Ferritin is a cytoprotective antioxidant strategy of the endothelium. Phagocyte-mediated oxidant damage to vascular endothelium is involved in various vasculopathies, including atherosclerosis and pulmonary leak syndromes. Heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells, increasing cytotoxicity from oxidants. However, brief heme exposure followed by prolonged incubation induces heme oxygenase and ferritin, which protect endothelial cells from oxidant injury. Ferritin, which stores iron and has ferroxidase activity, is the primary cytoprotectant. A site-directed mutant of ferritin lacking ferroxidase activity is ineffective. Endothelial cells exposed to heme induce ferritin synthesis, which protects against oxidant damage. Ferritin's protective effect is dose-dependent and involves iron sequestration. Apoferritin, when added to endothelial cells, is taken up and protects against oxidant-mediated cytolysis. Studies show that ferritin, not heme oxygenase, is the main cytoprotectant. Ferritin's ferroxidase activity and iron sequestration capacity are critical for its protective role. The study demonstrates that endothelial cells can be protected from oxidant damage through ferritin, an intracellular iron sequestrant. The findings suggest that ferritin plays a critical role in antioxidant defense by sequestering iron and preventing oxidative damage. The study also highlights the importance of ferritin in protecting endothelial cells from heme-induced oxidative stress. The results indicate that ferritin is a key factor in the endothelium's defense against oxidant damage.