Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease

Abstract

Increases in cell death by programmed (i.e., apoptosis, autophagy) or nonprogrammed mechanisms (i.e., necrosis) occur during tissue injury and may contribute to the etiology of several pulmonary or vascular disease states. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXalpha, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen-activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-kappaB, phosphatidylinositol 3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.

Figure 1. Relationship between the HO-1 system and cytoprotective functions

Heme oxygenase activity catalyzes the rate-limiting step in the oxidative catabolism of heme-b, to generate equimolar quantities of carbon monoxide (CO), biliverdin-IXα (BV), and ferrous iron. The reaction requires three moles of molecular oxygen (O₂) and reducing equivalents from NADPH: ferrihemoprotein (cytochrome p-450) reductase. The biliverdin-IXα generated is rapidly converted to bilirubin-IXα (BR) by NADPH biliverdin reductase (BVR). The iron generated in the HO reaction induces a compensatory elevation in the synthesis of ferritin, which sequesters the iron. The HO system provides cellular and tissue protection through the concerted action of these end-products, through anti-inflammatory, antiapoptotic, anti-proliferative, or anti-oxidative effects. Non-catalytic functions of BVR in the regulation of pro-survival cell signaling pathways have also been proposed.

Figure 2. Inhibition of apoptosis by HO-1 and its enzymatic products

Cells may undergo apoptosis by two major pathways, an extrinsic receptor-dependent pathway and an intrinsic (mitochondrial) apoptosis pathway, in response to various acute injurious stimuli. In the intrinsic pathway, environmental stress may cause direct mitochondrial damage, or promote signaling pathways dependent on ROS generation, resulting in the activation of Bax. Bax translocates to the mitochondrial outer membrane, where it oligomerizes or forms complexes with other proapoptotic Bcl-2 related proteins such as Bid or Bad. Bax oligomers form pores in the outer mitochondrial membrane, which facilitate the release of pro-apoptotic molecules such as cytochrome-c. Cytochrome c forms a complex with Apaf-1 and caspase-9, leading to caspase-9 activation. In extrinsic apoptosis, a death inducing ligand such as Fas ligand (FasL), initiates the death program upon interacting with its corresponding receptor (ie., Fas).These interactions lead to the recruitment and activation of caspase-8 in a death-inducing signal complex (DISC). Caspase-8 activation can lead to caspase-3 activation, or to the activation of Bid. Bid assists in the activation and mitochondrial translocation of Bax. Bid activation also results in the release of cytochrome c from the mitochondria. This diagram indicates those points in the apoptotic pathway at which HO-1 and its enzymatic products have been shown to inhibit cell death. Each number corresponds with an individual reference, and the shape of each symbol indicates which effector molecule has been implicated: HO-1, CO, BV/BR or ferritin/iron.