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Heme oxygenase-1: a therapeutic amplification funnel

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: 99 Brookline Ave., Boston, MA 02215, USA. E-mail: fritz_bach{at}hms.harvard.edu

HEME OXYGENASE-1 (HO-1) has emerged as a major "protective" gene, i.e., a gene that when expressed restores homeostasis in many situations by its anti-inflammatory, anti-apoptotic, and anti-proliferative actions (1) . The suggested use of HO-1 as a therapeutic is based on these attributes.

The effects of HO-1 expression are mediated by one or more of the products of HO-1 degradation of heme: carbon monoxide (CO), biliverdin, and free iron (Fe²⁺) (Fig. 1 ). Biliverdin is converted to bilirubin by biliverdin reductase and the Fe²⁺ leads to the opening of channels that export Fe²⁺ from the cell as well as up-regulation of ferritin, an iron binding protein. Each product has been shown to have at least some of the protective properties of HO-1 expression. CO, biliverdin, and bilirubin can be administered as such in vitro or in vivo. The action of ferritin is usually mimicked by use of an iron binding compound such as desferioxamine or apoferritin, although studies have been done using a recombinant adenovirus encoding the heavy chain of ferritin (2) . Most studies in vitro and in vivo have been done with CO or biliverdin/bilirubin. We and others recently reviewed HO-1 with respect to its actions as well as those of its products (1 , 3 , 4) .

View larger version (32K): [in this window] [in a new window]   Figure 1. HO-1 as a therapeutic funnel. HO-1 degrades heme into three products: carbon monoxide (CO), biliverdin, and Fe2+, as shown. One or more of these products mediates the function ascribed to each molecule flowing into the funnel. For example, after IL-10 has activated HO-1, the product(s) of HO-1 mediates the function of IL-10 even in the absence of IL-10. IL-10 cannot mediate its function in the absence of HO-1.

Studies substantiating a protective role for HO-1 have been mainly performed in mice and rats using the induction of HO-1 or the administration of CO or biliverdin/bilirubin, although there are few studies in pigs that are consistent with experiments in rodents (5 6 7) . These studies have included the effective prevention of the pathologies associated with atherosclerosis, balloon injury, chronic allograft rejection, TNF--induced hepatitis, ischemia-reperfusion injury, inflammatory lung disease, LPS-induced endotoxemia, ileus, pulmonary hypertension, and other conditions (1) .

In addition, the importance of HO-1 as a protective/therapeutic gene is supported by two groups of studies in humans. First, individuals vary in terms of the strength of their HO-1 response to a given stimulus based on a GT length polymorphism in the promoter of HO-1. Individuals with a "high" HO-1 response (short GT repeats) are less likely to have restenosis after balloon angioplasty, as well as less likely to have chronic rejection of an allograft (8) and to undergo other pathological processes (9 10 11) . Individuals with longer GT repeats, who respond more weakly in terms of up-regulating HO-1 activity to a particular stress stimulus, are more likely to experience restenosis or chronic rejection. Thus, the ability to up-regulate HO-1 more strongly to a specific stress stimulus appears to be physiologically important. Second, multiple studies show that individuals with high normal or just above normal levels of bilirubin, which is produced as a consequence of HO-1 action, have less atherosclerosis-related diseases than individuals with low normal levels of bilirubin (12) . The combination of these association studies with experimental findings that administration of either CO or biliverdin suppresses atherosclerosis-related pathologies in rodents strongly supports the importance of HO-1, bilirubin, and CO as protective products in humans.

The animal studies have for the most part tested the ability of HO-1 to prevent a pathological process, i.e., HO-1 was induced before a disease-precipitating stress. Most disorders in which induction of HO-1 activity was advantageous have involved an inflammatory component.

My goal in this article is to discuss two well nigh unique attributes of HO-1 function. First, HO-1 functions to mediate the therapeutic effects of other molecules such as IL-10, the anti-inflammatory cytokine, rapamycin, 15-PGJ₂, and aspirin. I have referred to this as HO-1 functioning as a "therapeutic funnel" (Fig. 1) . For instance, IL-10 stimulates the up-regulation of HO-1, then a product(s) of the degradation of heme by HO-1 mediates the therapeutic effect of IL-10. As we define it, a given molecule only functions "via the HO-1 funnel" if both of two conditions obtain: the molecule functions only when HO-1 is present and induced and a product(s) of HO-1 can mediate the functions ascribed to the "given molecule" in the absence of that other molecule. Second, HO-1 can amplify the therapeutic effects of the other molecule.

There are now an impressive number of molecules that appear to function via the HO-1 funnel (Fig. 1) ; for some of these there is evidence that the funnel allows the amplification of the effects ascribed to the other molecule (discussed below). There is no commonality among these molecules, which have diverse chemical structures ranging from proteins to small organic compounds to a gas molecule (NO). The first example of a molecule that was shown to act via the HO-1 funnel was interleukin 10 (IL-10), a potent anti-inflammatory molecule acting on monocyte-macrophages and other cells. IL-10 suppresses TNF- expression in stimulated macrophages. The suppression requires the presence of HO-1 (13) . Moreover, even in the absence of IL-10, either expression of HO-1 or administration of CO or biliverdin to the monocyte-macrophages had the same effects as IL-10. Paralleling the in vitro findings are in vivo studies showing that the protective effect of IL-10 in a lethal endotoxic shock model is dependent on the expression of HO-1; HO-1, CO, or biliverdin can each replace the effects of HO-1 in the absence of IL-10 (13) .

Other examples of protective molecules that function via HO-1 follow. In each case, the molecule can only mediate its effects in the presence of HO-1, and one or more of the products of HO-1 can reproduce the effects of the molecule in question without that molecule being present. 1) Rapamycin has an anti-proliferative effect on smooth muscle cells (14) . Induced expression of HO-1 or administration of CO or biliverdin reproduces the effects of rapamycin (15) . 2) Both the protective effects of CO and those of NO in a model of TNF-/D-galactosamine-induced hepatitis require expression of HO-1 (15) . 3) Two groups have shown that the effects of prostaglandin J2 can only be mediated if HO-1 is expressed (16 , 17) . 4) The anti-inflammatory effects of alcohol in macrophages resulting in suppression of TNF- and a boosting of IL-10 are dependent on HO1 expression (G. Szabo, personal communication). HO-1 and CO have the same effects in the absence of alcohol. It is tempting to speculate that the beneficial effects of imbibing moderate levels of red wine or alcohol in general are due to the induction of HO-1 by the alcohol (18) . 5) Though less clearly demonstrated, it appears that heat shock proteins that have protective functions may work via the expression of HO-1 (19) . 6) VEGF (20) , aspirin (21) , probucol (22) , and simvastatin (23) have all been shown to be dependent on the expression of HO-1, with products of HO-1 being able to mediate the actions of these molecules. These various molecules that feed into the HO-1 funnel function by several quite disparate mechanisms. Finally, however, the therapeutic effect appears to be mediated by HO-1 and its products.

Discussing these examples of molecules that appear to mediate their effects via HO-1 does not imply that all "protective" molecules will do so. Nor does it necessarily suggest that a molecule that functions via HO-1 in some cells will do so in all. For instance, probucol, which appears to function via HO-1 in smooth muscle cells, can function without HO-1 in endothelial cells (22) , and simvastatin uses HO-1 to achieve its function in vascular smooth muscle cells but does not involve HO-1 in endothelial cells or macrophages (23) . An earlier version of the funnel idea was presented as a part of a review at a time when there were only six substances described as using the HO-1 funnel. That report did not deal with the ideas below (1) .

So far I have focused on the funneling aspects of HO-1. There is, however, another aspect of these findings that could have import: the HO-1 funnel can amplify a therapeutic effect. I discuss three different mechanisms by which amplification might occur. First, the effects of IL-10 on macrophages (discussed above) can illustrate one prototype amplification loop, which might also function for other molecules. A stress (proinflammatory) stimulus will lead to up-regulation of proinflammatory cytokines and HO-1 in macrophages. As a result, CO will be produced. Administration of CO to macrophages exposed to a proinflammatory stimulus boosts the production of IL-10 in addition to suppressing proinflammatory cytokines (24) . IL-10 induces HO-1 (14) . Thus, the cycle is established: IL-10 leads to up-regulation of HO-1, which leads to production of CO, the presence of which leads to increased IL-10 synthesis, etc. The initial preferential production of IL-10 is amplified as the cycle (HO-1COincreased IL-10 productioninduction of HO-1) continues. The same argument just made for IL-10 has been made for VEGF (25) . Whether such a cycle shuts off when the inflammatory stimulus is no longer present or whether there are negative regulatory controls is not clear.

A second mechanism by which the HO-1 funnel can amplify the effect of a given molecule can be illustrated by the funneling of CO and NO action. Either CO or NO can ameliorate hepatitis induced by TNF- plus D-galactosamine (16) . However, for the therapeutic effect of CO to manifest, there is the requisite sequential activation by CO of NF-B, of iNOS with production of NO, and the induction of HO-1 by NO. If any of these steps are blocked, CO has no therapeutic effect. Likewise, the beneficial effects of NO require induction of HO-1 (16) . We have now found that biliverdin appears to mediate the effects of either CO or NO. Biliverdin exerts therapeutic effects without requiring the further action of CO, NF-B, iNOS, or HO-1 (unpublished observations). Thus, as the CO NF-B iNOS/NO HO-1 CO cycle continues, there is continuing production of biliverdin, which is therapeutic. A possible advantage of initiating the cycle with CO rather than giving biliverdin directly would be that the cycle is set in motion and there is continuing production of biliverdin. Whether such a cycle exists in other situations in which CO provides beneficial effects is unknown. In fact, anytime a product of HO-1 action such as CO or biliverdin can lead to up-regulation of HO-1, directly or indirectly, there is the potential for an amplification loop.

Third, as biliverdin is administered or presumably when produced endogenously, biliverdin reductase is induced and may function as a transcription factor leading to the induction of HO-1 (26) . To the extent that biliverdin induces HO-1, this amplification mechanism would be functional in all cases when HO-1 is up-regulated. In addition to these potential amplification cycles, there is the biliverdin-bilirubin cycle proposed by Sedlak and Snyder (27) .

To the extent that such amplifying cycles function in stress situations, they would help maintain the effects of even a short treatment. As such, the need for treatments with CO, for instance, might be less frequent than predicted by the half-life of CO. This is suggested in the works by Sarady et al. and Otterbein et al. that demonstrate that a short exposure (1 h) to CO is sufficient to elicit long-term protection in models of endotoxic shock and balloon angioplasty (28 , 29) .

There may be therapeutic implications in the case of molecules that function by up-regulating HO-1 and where a product of HO-1 appears to have the "same" effects as the therapeutic. An example of this is use of rapamycin-coated stents to prevent restenosis. As mentioned above, rapamycin inhibits smooth muscle cell proliferation via HO-1 and intimal hyperplasia in vivo (30) ; both CO and biliverdin/bilirubin are able to inhibit smooth muscle cell proliferation without rapamycin being present (28) . Thus, rapamycin acts via the HO-1 funnel leading to the production of CO and/or biliverdin. Might there be an advantage to use biliverdin or CO, which are presumably the molecules that most directly mediate the therapeutic effect of preventing intimal hyperplasia, rather than rapamycin, which acts from a greater distance (molecularly speaking). Rapamycin may have effects that are not particularly desirable other than up-regulation of HO-1. Two of the breakdown products of rapamycin are CO and NO, both of which can up-regulate HO-1 (31) .

One can only speculate why any one gene would assume such great importance as the funnel amplification idea suggests for HO-1. A possible reason might be that HO-1 appears to have four different mechanisms to overcome stress. The first is removal of excess heme, which if not removed would lead to oxidative stress. The other three are related to the three products of HO-1 degradation of heme. These three products mediate their protective functions in a complementary manner, making available three approaches to combating stress. Their combined presence could lead to additive or even synergistic effects. There are several lines of evidence that support the idea that the different products may function by different mechanisms (32 , 33) . First, we have noted that some conditions are aided by one product but not by another. Admittedly, such findings this early in the evolution of the field may be a matter of improper dosing of the compound that appears not to provide protection. Second, and more persuasive are our studies of CO and biliverdin as therapeutics to prevent ischemia-reperfusion injury of small intestinal transplants (31 , 32) . While these agents both protect in that they decrease inflammation and maintain function of the muscularis of the intestine (diminish ileus), they appear to do so at least in part by affecting different components of the pathology that leads to injury (31 , 32) . For instance, while CO increases blood flow and biliverdin does not, biliverdin inhibits the up-regulation of endothelial cell adhesion molecules and thus diminishes cellular infiltration whereas CO does not (34) . We have recently obtained similar evidence for the signaling pathways used by CO and biliverdin/bilirubin in suppressing vascular smooth muscle cell proliferation and intimal hyperplasia after balloon angioplasty in rats. Although both agents do so, they affect different parts of the signaling apparatus involved in regulating proliferation. For instance, CO induces p38 MAPK activation, which is essential for the inhibition of proliferation. Bilirubin, on the other hand, suppresses p38 MAPK to inhibit proliferation. Similar effects of HO-1 up-regulation have been demonstrated (6) . Third, we have found that in some situations, the combined presence of biliverdin and CO can lead to an additive, perhaps even synergistic effect. Whether these findings with exogenously administered molecules apply to the endogenous reactions is unknown.

There are fascinating and important issues to resolve with regard to HO-1. There is a need further to investigate fundamental mechanisms by which expression of HO-1 and administration of its individual products exert their effects. In addition, there are questions about how best to utilize this system for the treatment of relevant disorders/diseases. One argument would have it that all three products have salutary actions and so why not just overexpress HO-1? Alternatively, it could be that administration of a product(s) in higher amounts than could be generated by inducing HO-1 would be most advantageous. Investigations to resolve some of these issues would seem all the more important given the funneling and amplification properties of HO-1 discussed above. The HO-1 system appears to play a central and critical role in regaining and maintaining homeostasis in some important disorders affecting the human population.

Received for publication December 2, 2004. Accepted for publication March 30, 2005.

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