Hypoxia-inducible factor-1 in myocardial ischaemia/reperfusion injury

In this issue of Acta Physiologica, Xie et al.1 describe the protective role of hypoxia-inducible factor-1 (HIF-1) against myocardial ischaemia/reperfusion injury in diabetic rats. This study demonstrates that HIF-1 signalling pathway is impaired in diabetes, abolishing the cardioprotective effect of sevoflurane post-conditioning; the administration of deferoxamine re-activates HIF-1 conferring cardioprotection. Myocardial ischaemia refers to impaired blood supply to heart muscle caused by partial or total obstruction of arterial inflow. Early re-establishment of cardiac blood flow represents the keystone of all current treatment options to myocardial ischaemia; nonetheless reperfusion may paradoxically trigger ischaemic tissue damage, leading to ischaemia/reperfusion injury (IRI). Several mechanisms underlying IRI development are described as follows: (1) prolonged ischaemia causes ATP depletion and intracellular acidosis resulting from mitochondrial impairment, anaerobic metabolism and lactate accumulation, followed by dysfunctional ATPase-dependent ion transport mechanisms, intracellular and mitochondrial calcium overload, cell swelling and death by necrosis, apoptosis and autophagy; (2) reperfusion is characterized by overproduction of reactive oxygen and nitrogen species (ROS, RNS) as well as tissue infiltration by pro-inflammatory neutrophils.2 The HIF transcription factors are master regulators of hypoxia-responsive genes. HIF is a heterodimer of constitutively expressed α and β subunits; β subunit is independent of [O2], whereas protein stability of the α subunit is sensitive to cellular O2 levels: during normoxia, it is degraded through a process involving hydroxylation of conserved proline residues in an oxygen-dependent degradation domain. Proteasome-mediated degradation at normoxia represents a further mechanism of HIF regulation. Ischaemic post-conditioning is an endogenous protective mechanism against myocardial IRI, characterized by transitory coronary occlusions and reperfusions promptly before restoration of cardiac blood flow after prolonged ischaemia. Although this mechanism is effective in reducing ischaemic cardiac damage, its clinical application is limited because of ethical and practical problems. As a consequence, a valid alternative is provided by pharmacological post-conditioning, consistent in the administration of various pharmacological agents at the time of reperfusion. A large number of studies indicate that inhalational anaesthetics, such as sevoflurane and isoflurane, can relieve IRI. In particular, anaesthetic post-conditioning with sevoflurane reduces myocardial infarct size, attenuates cardiomyocyte apoptosis and improves mitochondrial respiratory function by activation of several cardioprotective signalling pathways, such as the phosphatidylinositol-3-kinase (PI3K)/Akt and the Janus kinase signalling transduction/transcription activator (JAK2–STAT3).3, 4 In the study by Xie et al.1 the cardioprotective effect of sevoflurane post-conditioning in myocardial IRI is dependent on the upregulation of HIF-1α. The Authors describe that the beneficial effects of sevoflurane post-conditioning against myocardial IRI are associated to mitochondrial ultrastructure/function preservation. Nevertheless, the beneficial properties of sevoflurane post-conditioning observed by Xie et al.1 are not described in diabetic rats. In fact, HIF-1 signalling pathway is less active in both animal models and patients affected with diabetes mellitus. An important explanation is provided by the interference of hyperglycaemia with HIF-mediated cellular adaptation to hypoxia, which impairs HIF-1α protection against proteasome-mediated degradation.5 Xie et al.1 demonstrate that the stimulation of HIF-1 signalling pathway by deferoxamine – an iron chelator able to activate HIF-1 and to increase expression of its target genes – improves mitochondrial function and reduces both ROS production and apoptosis in myocardial cells of diabetic rats subjected to IRI. The main findings of this study strengthen the idea that activation of HIF by sevoflurane is crucial for cardioprotection in myocardial IRI. We could question whether these observations may be extended to other organs. For instance, it is interesting to note that the pharmacological activation of HIF limits diabetes-induced alterations in renal oxygen metabolism and mitochondria function, preventing the onset or progression of diabetic nephropathy.6 Furthermore, sevoflurane post-conditioning applied to a rodent model of focal cerebral IRI is able to reduce brain infarct size and neuronal apoptosis by a mechanism partly mediated by PI3K/Akt pathway via the upregulation of HIF-1α.7 Nevertheless, our group described that the association of inhaled sevoflurane anaesthesia with HIF-1α activation in rats exposed to hepatic IRI is not associated with reduced liver damage or mitochondrial dysfunction; on the contrary, a limitation of HIF-1α by intravenous propofol anaesthesia provides hepatoprotection and mitochondrial improvement.8 The reasons why sevoflurane-dependent HIF-1 activation does not exert protective effects in hepatic IRI are not fully clarified and merit further investigation. Sevoflurane administration alters the hepatic mitochondria respiratory chain activity, and it is also possible that the inorganic fluoride resulting from hepatic metabolism of sevoflurane could modify ROS production and induce oxidative damage. Moreover, as HIF-1 displays an organ-specific regulation under hypoxia, it is conceivable that its activation could regulate different downstream pathways with divergent clear-cut final effects. Such variations may be also dependent on the regenerative potential of different tissues. Future research will be aimed to clarify these aspects in order to provide investigators with new keystones on which to build clinical studies. The author has no conflict of interest to declare. Francesco Bellanti is co-funded by the Development and Cohesion Fund (Grant no. 2007IT051PO005) – APQ Research Regione Puglia (Future in Research project).