Iron-derived
reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including
atherosclerosis, microangiopathic
haemolytic anaemia,
vasculitis and
reperfusion injury. One abundant source of redox-active
iron is
haem, which is inherently dangerous when released from intracellular
haem proteins. The present review concerns the likely involvement of
haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to
haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free
haem also promotes the conversion of
low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of
haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer
haem to endothelium, thereby enhancing cellular susceptibility to
oxidant-mediated injury. As a defence against such toxicity, upon exposure to free
haem, endothelial cells up-regulate
haem oxygenase-1 and
ferritin.
Haem oxygenase is a
haem-degrading
enzyme that opens the
porphyrin ring, producing
biliverdin,
carbon monoxide and a most dangerous product-free redox-active
iron. The latter can be controlled effectively by sequestration within
ferritin, a multimeric
protein with a very high capacity for storing
iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous
haem and
oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with
haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.