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  • Ischaemia inevitably results in local hypoxia which elicits


    Ischaemia inevitably results in local hypoxia, which elicits a hypoxic response in the affected tissue and neighbouring region. HIF signalling is stimulated in these hypoxic conditions [125]. This allows increased expression of its target genes, which leads to a range of beneficial effects including angiogenesis and the aforementioned metabolic adaptations to hypoxia. This response is key in supporting the tissue to cope with the ischaemic insult and alleviate the subsequent deleterious longer-term effects of ischaemia-reperfusion. HIF-1 activity has been shown to increase early following MI, in ventricular biopsies from patients undergoing coronary bypass surgery [138]. Studies using coronary ligation in the rat heart showed increased expression of HIF-1α protein and HIF-1 targets mRNA over the first week following infarction [26]. In addition, Wei et al. found that HIF-1α conditional KO mice quickly developed cardiac hypertrophy and decompensation when subjected to pressure overload, and concluded that HIF-1 plays a crucial role in protecting the myocardium in the development of hypertrophy [139]. In line with this, Cai et al showed that protective effect of intermittent hypoxia was lost in HIF-1α +/− mice [140]. In contrast, work in a transgenic mouse model of constitutively active HIF-1α showed reduced infarct size and improved cardiac function four weeks after coronary ligation [141]. The activation of HIF-1 in endothelial Iberiotoxin during hypoxia or ischaemia is equally crucial to the subsequent recovery of the heart. As well as having metabolic oxygen sparing effects on the endothelium, HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of angiogenic factors. A genetic model of prolyl hydroxylase inhibition showed that activation of HIF-1 signalling in endothelial cells resulted in improved LV function and survival following ischaemia-reperfusion [142]. Furthermore, a lack of concordance between myocardial growth and endothelial angiogenesis has been shown to contribute to the development of heart failure [143]. Angiogenic HIF-1 targets such as VEGF are responsible for the fast growth of collateral vessels and have been implicated in cell survival following myocardial infarction [138,144]. Polymorphisms in the HIF-1α locus have been associated with reduced collateral vessel formation, affecting the progression of ischaemic disease [145]. Furthermore, expression of target genes VEGF and HO-1 have been shown to mediate the all-important improvement in cell survival following ischaemia-reperfusion [120,141,146]. Though the initial response mediated by hypoxic signalling protects the myocardium by improving oxygen delivery and preventing oxygen waste, it remains unclear whether the hypoxia response is beneficial in the longer term, as it has become apparent that angiogenic stimuli induce hypertrophy [147]. It is clear that HIF-1 signalling is increased in the initial stages of hypertrophy, but it may not be the case in prolonged hypoxia, as shown in models of pressure overload [146]. This mismatch between persistent hypoxia and decreased HIF-1 signalling could be at the core of the damage and dysfunction observed in the failing heart [147]. Although the role and effects of HIF-1 have been extensively studied over the past two decades, as it was the first identified of this family of transcription factors, the complimentary and contrasting roles of HIF-2 and HIF-3 remain relatively poorly understood to date. For instance, HIF-2 has been shown to have no effect on glycolysis, unlike HIF-1 [9]. Generally, HIF-2 has been found to have effects particularly on longer term adaptation to hypoxia, suggesting a sort of takeover from HIF-1 to HIF-2 with prolonged periods of hypoxia, which appears to be mostly focused on mitochondrial homeostasis [148]. Studies in KO mice suggest HIF-2 may also be important in affecting cell survival during I/R through the regulation of cellular antioxidant capacity [149]. HIF-3 poses a more complex problem to investigate, given that there are alternatively spliced variants of the HIF-3α subunit, adding up to at least seven isoforms [150]. Very little is known about the effects of HIF-3 signalling in the heart. Importantly, HIF-3 has a role in attenuating the activity of HIF-1α, also acting in the transition from HIF-1 to HIF-2 to HIF-3 in sustained [151] hypoxia.