The Biology of Heme Oxygenase During Development

Abstract

After completing this article, readers should be able to: 1. Describe the physiologic effects of the heme oxygenase reaction. 2. Delineate the potential role of heme oxygenase-1 in fetal growth. 3. Describe the effects of heme oxygenase-1 on growth factors in the placenta. 4. Delineate the potential role of heme oxygenase-1 in the developing lung. Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme (Fig. 1⇓ ). This reaction previously was believed to be strictly catabolic. However, it is unique because it forms carbon monoxide (co), previously believed to be only a poison, but now understood to be a neurotransmitter and a vasodilator with nitric oxide-like properties.1,2 Another byproduct of the HO reaction is iron, which can regulate many genes.3,4 Bilirubin formed from HO is an antioxidant, as demonstrated in vitro and in vivo.5,6 Therefore, the HO reaction has varied physiologic effects. Figure 1. Metabolic reaction of heme oxygenase. Heme from senescent red blood cells (RBC) and from hemoproteins is degraded by heme oxygenase in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and cytochrome c (P450) reductase. Iron (Fe++) is released from the reaction, as is carbon monoxide (CO) and biliverdin. The former can activate guanylate cyclase (GC) to form cyclic guanosine 3′,5′-monophosphate (GMP). Biliverdin is reduced further to bilirubin by biliverdin reductase. Hb=hemoglobin, Mb=myoglobin, NOS=nitric oxide synthetase. There are three forms of HO. The HO-1 enzyme is induced by oxidant stress, such as caused by heavy metals and inflammation. This is a generalized response to oxidative stress, and HO-1 is referred to as a stress response gene.7Because HO-2 is inducible only by glucocorticoids,8 it is believed to be the constitutive isoenzyme. Most recently identified is HO-3,9 which may serve as a regulator of heme, as is …