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  • There is a growing body of

    2019-07-11

    There is a growing body of evidence for impaired HIF-1 activation in diabetes, though there is still some controversy. Specimens of human heart tissue in angina and biopsies from coronary bypass surgery showed decreased HIF-1α and VEGF levels in type 2 diabetic patients compared to non-diabetics [152]. Work in streptozotocin-induced diabetic rats showed increased infarct size in hyperglycaemic rats, which correlated with decreased levels of HIF-1α [153,154]. A negative correlation has been identified between cardiac HIF-1α levels and glycaemic control in patients with type 2 diabetes and in STZ-induced diabetic rats [154,155]. We have recently demonstrated that the mechanism behind HIF-1α impairment in diabetes is of metabolic origin, driven by increased fatty acids. This elevated dependence on fatty Ac-DEVD-CHO metabolism suppresses glycolysis, which results in downregulation of myocardial succinate in hypoxia, resulting in decreased HIF-1α stabilisation [42]. It has also been suggested that HIF-1β impairment could precede the development of type 2 diabetes [156]. Studies in both animal models and patients with type 2 diabetes have shown decreased glucose uptake, glycolytic rates, collateral blood vessel formation, and increased ROS production compared to healthy hearts in response to ischaemia [[157], [158], [159], [160], [161]]. We have shown that in response to in vivo chronic hypoxia, type 2 diabetes decreases the upregulation of glycolysis, limits downregulation of fatty acid oxidation, Ac-DEVD-CHO and prevents mitochondrial adaptation [97]. Together, these studies suggest abnormal HIF-1α activity in the diabetic heart, correlating with impaired functional recovery when stressed [153]. One study showed that HIF-1α overexpression in mice prevented cardiac remodelling in diabetic mice [162]. Gu et al. showed that the HIF-1α Pro582Ser polymorphism could confer protection against diabetic nephropathy, by preventing the negative effect of glucose on HIF-1 signalling, suggesting a beneficial effect of HIF-1 on the microvasculature [163].
    Therapeutic use of HIF activation HIF-1 activation has already been proven to have therapeutic potential in the context of myocardial ischaemia, through the use of ischaemic pre-conditioning. When tissue is given short bursts of ischaemia-reperfusion before an ischaemic insult, survival is improved and this has been linked to upregulation of the HIF signalling pathway [164]. In a HIF-1α deletion mouse study, when mice underwent pre-conditioning, the infarct size was reduced in control mice but this was not observed in mice with the HIF-1α deletion [165]. Furthermore, genetic studies using gene silencing to prevent PHD activity led to attenuated ischaemia-reperfusion injury in the heart [166]. HIF-1α -activating pharmacological compounds fall into one of several classes, all of which have their effect by preventing HIF-1α degradation. Examples of these are listed in Table 1. 2-OG mimetics have been used as tool compounds in pre-clinical studies. Pre-treatment with dimethyloxalylglycine (DMOG) in a rabbit model of myocardial ischaemia-reperfusion resulted in a significant decrease in the resulting infarct size following reperfusion [167]. Similarly, hearts from rats pre-treated with DMOG showed improved functional recovery following ischaemia-reperfusion in an ex vivo perfused heart setup [168]. In most studies these compounds were administered before the onset of injury or ischaemia, which could put in question their usefulness in a clinical setting. They have also been criticised for their poor selectivity and risk of off-target effects due to their inhibition of other 2-OG dependent enzymes [38,169]. Iron chelators such as desferrioxamine and hydralazine, have been shown to have HIF-1α stabilising properties through PHD inhibition. Desferrioxamine treatment was shown to improve brainstem blood flow and reduce vasospasm in a rat model of aneurysmal subarachnoid haemorrhage [170]. However, new generation PHD inhibitors have since been developed, several of which are undergoing clinical trials for use in conditions such as anaemia associated with renal disease, inflammatory disease, or brain haemorrhage (Table 1). With regards to potential for cardiovascular disease, chronic PHD inhibition strategies have already shown potential in rodent models of heart failure. Treatment with orally-active PHD inhibitor GSK360A resulted in increased expression of HIF targets, accompanied by improved recovery post MI in rats with established heart failure, showing long term improvements in remodelling and left ventricular function [171]. Roxadustat (FG-4592) has completed Phase I and Phase II trials for use in anaemia, and showed good tolerability, improved circulating haemoglobin, as well as decreased total cholesterol levels, independent of the use of lipid-lowering agents [[172], [173], [174]]. Another orally-available PHD inhibitor [175], Molidustat (BAY85-3934), has completed Phase II clinical trials for treatment of anaemia associated with chronic kidney disease (DIALOGUE trial, NCT02021370), and Phase III clinical trials are currently recruiting (NCT03351166). Vadadustat (AKB-6548) has also undergone Phase II clinical trials, where it showed enhanced iron mobilisation and haemoglobin in patients with chronic kidney disease [176], and showed no significant changes in blood pressure, VEGF or total cholesterol levels [177]. JTZ-951, a recent clinical PHD inhibitor, has completed Phase II clinical trials (NCT01971164), showing safety and tolerability, with improved haemoglobin levels in patients with end-stage renal disease [178]. Some preliminary work has been done which suggests that HIF-1α activation can also be beneficial in diabetes. The clinical PHD inhibitor, Daprodustat (GSK1278863), has now completed Phase I clinical trials for treatment of diabetic foot ulcer (NCT01831804), as well as perioperative ischaemia, suggesting that repurposing of these compounds for use in cardiovascular disease may not be far.