Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jul 1;47(1):1-12.
doi: 10.1016/j.freeradbiomed.2009.04.007. Epub 2009 Apr 9.

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

Danielle Morse  1 , Ling Lin, Augustine M K Choi, Stefan W Ryter
Affiliations
Review

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

Danielle Morse et al. Free Radic Biol Med. .

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.

PubMed Disclaimer

Figures

Figure 1
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 2006;86:583–650. - PubMed
    1. Morse D, Choi AM. Heme oxygenase-1: the “emerging molecule” has arrived. Am. J. Respir. Cell Mol. Biol. 2002;27:8–16. - PubMed
    1. Ryter S, Otterbein LE, Morse D, Choi AM. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol. Cell. Biochem. 2002;234–235:249–263. - PMC - PubMed
    1. Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J. Biol. Chem. 1969;244:6388–6394. - PubMed
    1. Poss KD, Tonegawa S. Heme oxygenase-1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. USA. 1997;94:10919–10924. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources