Heme oxygenase‐1 in growth control and its clinical application to vascular disease

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Abstract
Heme oxygenase‐1 (HO‐1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO‐1 originally centered on its heme‐degrading function, recent findings indicate that HO‐1 exerts other biologically important actions. Emerging evidence suggests that HO‐1 plays a critical role in growth regulation. Deletion of the HO‐1 gene or inhibition of HO‐1 activity results in growth retardation and impaired fetal development, whereas HO‐1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO‐1 are not well established, HO‐1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO‐1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO‐1 are highly variable and may reflect a role for HO‐1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO‐1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO‐1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO‐1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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