Heme oxygenase‐1‐derived carbon monoxide protects hearts from transplant‐associated ischemia reperfusion injury

Abstract

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. Rat hearts, exposed to a prolonged period (24 h) of cold (4 degrees C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO-1 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO-1 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO-1. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO-1. This was associated with a significant reduction in the number of cells undergoing apoptosis in the graft with no apparent decrease of intravascular fibrin polymerization, platelet aggregation, or P-selectin expression. In conclusion, HO-1-derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. The observation that exposure of the donor and the graft to CO is sufficient to afford this protective effect should have important clinical implications in terms of preventing IRI associated with heart transplantation in humans.

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

“…A number of recent studies demonstrating that exogenous low-dose CO at similar concentrations to those used here can provide potent cytoprotective effects have been reported in models of lung and hepatic injury, airway inflammation, and cardiac transplantation (2,32,39,57). In the bleomycininduced lung injury model, overexpression of HO-1 gene or administration of exogenous CO inhibits development of pulmonary fibrosis (46,56).…”

A new activating role for CO in cardiac mitochondrial biogenesis

“…Second, COHb delays endogenous CO clearance both by decreasing the PO 2 level and by increasing the gas back-pressure in tissue (Cronje et al, 2004). This is a simple explanation for the rapid cytoprotection by CO that may recapitulate HO-1 induction (Akamatsu et al, 2004;Fujita et al, 2001). CO and hypoxia also induce HO-1 and mitochondrial heme release (Cronje et al, 2004;, and heme oxygenase inhibition attenuates Akt activation, thus also implicating endogenous CO in mitochondrial biogenesis.…”

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

“…The cytoprotective properties of HO-1 have traditionally been attributed to the by-products of heme degradation, namely bilirubin and carbon monoxide (CO). Indeed, within a narrow therapeutic range, these catalytic by-products exert powerful antioxidant [15,31], antiinflammatory [32] and anti-apoptotic effects [33][34][35], leading to reduced infarct size [16,17,[36][37]. However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38.…”