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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online February 20, 2004 as doi:10.1096/fj.03-0921fje. |
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,2
* Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA;
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; and
Instituto Gulbenkian de Ciência, Oeiras, Portugal
2Correspondence: Inflammation laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal. E-mail: mpsoares{at}igc.gulbenkian.pt.html
SPECIFIC AIMS
Heme oxygenase-1 (HO-1) degrades heme into iron, biliverdin, and carbon monoxide (CO). HO-1 expression can be used therapeutically to ameliorate undesirable consequences of ischemia reperfusion injury (IRI) but the mechanism by which this occurs remains to be established. The hypothesis tested here was that CO contributes in a critical manner to mediate the protective effect of HO-1.
PRINCIPAL FINDINGS
1. Exogenous CO protects rat hearts from prolonged ischemia reperfusion injury
Six of six hearts harvested from untreated rats and exposed to prolonged (24 h) cold (4°C) ischemia failed to function after transplantation into syngeneic recipients (0% survival) (Table 1
). Induction of HO-1 expression by administration of CoPPIX to the donor restored graft function, i.e., five of six hearts functioned upon transplantation into syngeneic recipients (83% survival) (Table 1)
. Induction of HO-1 expression by CoPPIX was confirmed at the protein level by Western blot and immunocytochemistry (data not shown). Similar results were obtained using semiquantitative RT-PCR (data not shown). Administration of the HO enzymatic inhibitor zinc protoporphyrin IX (ZnPPIX) at the time of transplantation abolished the protective effect of HO-1 (0% survival, n=6) (Table 1)
. This set of observations suggests that HO-1 enzymatic activity is required for the protective effect of HO-1.
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We then asked whether CO, one of the end products of heme catabolism by HO-1, could account for the protective effect of HO-1. When CO was administered to the donor and to the recipient (400 ppm) as well as during ischemia (the graft was stored in 1% CO-saturated UW solution), five of six hearts survived after transplantation into syngeneic recipients (83% survival) (Table 1)
, a result mimicking that obtained with up-regulation of HO-1 by CoPPIX (Table 1)
. This suggests that the protective effect of HO-1 can be mediated via CO.
We analyzed the relative contribution of CO administration to the donor, to the graft during the period of ischemia, and/or to the recipient in preventing IRI. When CO was administered to the donor without further treatment, two of six grafts functioned after transplantation into syngeneic recipients (33% survival) (Table 1)
. Similar results were observed when hearts were exposed to CO during ischemia without further treatment: two of six grafts functioned after transplantation into syngeneic recipients (33% survival) (Table 2
). When CO was administered to the donor and to the graft during ischemia, four of six grafts functioned after transplantation (66% survival) (Table 2)
. Administration of CO to the recipient without further treatment or in combination with CO administration to the donor and/or the graft during ischemia did not show a significant additional affect compared with CO administration to the donor and the graft (Table 2)
.
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2. Exogenous CO prevents myocardial cells from undergoing apoptosis after IRI
Based on the demonstration that CO can act in an anti-apoptotic manner and given the deleterious effects of cardiomyocyte apoptosis in IRI, we asked whether the protective effect of CO would be related to its anti-apoptotic effect. We found that this is the case. In untreated hearts exposed to ischemia, there was extensive apoptosis of myocardial cells detected 10 min after transplantation into syngeneic recipients (data not shown). Up-regulation of HO-1 by the administration of CoPPIX to the graft donor reduced the number of apoptotic cells in a significant manner compared with untreated controls (P<0.05) (data not shown). Administration of exogenous CO to the donor and to the graft during ischemia mimicked the effect of HO-1 in inhibiting apoptosis (data not shown).
CONCLUSIONS AND SIGNIFICANCE
There is now extensive evidence showing that expression of HO-1 protects hearts from ischemia reperfusion injury. The mechanism by which this occurs is unclear. The finding that exogenous CO appears fully able to substitute for HO-1 in preventing IRI of transplanted hearts suggests that CO accounts in large measure for the protective effect of HO-1 (Table 1)
. Our present data also suggests that CO exerts this effect by protecting cells in the ischemic heart from undergoing apoptosis (data not shown). Exposure of the donor to CO is sufficient to afford a significant level of protection from IRI (Table 2)
. This effect is further enhanced when the graft itself is exposed to CO during the period of ischemia (Table 2)
. On the other hand, exposure of the recipient to CO at the time of reperfusion does not afford a significant improvement in protecting hearts from IRI (Table 2)
. This strongly suggests that the anti-inflammatory effect of CO such as exerted at the level of the recipients’ circulating leukocytes and platelets is not the central mechanism by which the protective action of CO is exerted in IRI. We propose that CO may have a "preconditioning" type of effect in that it triggers signaling transduction pathways that protect cells in the ischemic heart (endothelial cells and cardiomyocytes) from undergoing apoptosis (data not shown). Presumably the protective effect of CO relies on its ability to sustain the viability of a critical mass of cardiomyocytes, essential to ensure cardiac function after transplantation. A schematic representation of this phenomenon is illustrated in Fig. 1
. The finding that exposure of the donor and the graft to exogenous CO is sufficient to afford this protective effect might have important clinical implications in preventing IRI associated with organ transplantation in humans.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0921fje; doi: 10.1096/fj.03-0921fje 
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