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Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood–brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke.

Gliptins are a novel class of oral antihyperglycaemic agent that inhibit dipeptidyl peptidase 4. Professor Scheen describes the pleiotropic beneficial effects of these drugs, beyond basic glycaemic control in patients with type 2 diabetes mellitus, to emerging data and ongoing trials on cardiovascular protection in patients with ischaemic heart disease or congestive heart failure. Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II–III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile. Key Points Dipeptidyl peptidase 4 (DPP-4) inhibitors (gliptins) are incretin-based drugs with a role in the management of type 2 diabetes mellitus; they improve glucose control without inducing hypoglycaemia or weight gain Gliptins not only increase the level of glucagon-like peptide 1, but also the concentration of other peptides that might exert vasoactive, and possibly cardioprotective, effects Gliptins exert pleiotropic actions in patients with type 2 diabetes, resulting in favourable effects on postprandial glycaemia and lipaemia, blood pressure, silent inflammation, oxidative stress, and endothelial dysfunction Post-hoc analyses of phase II–III, controlled trials showed no cardiovascular harm with gliptins compared with placebo or other antihyperglycaemic agents, and possibly indicated a cardiovascular protective effect Large, prospective trials involving >40,000 high-risk patients with type 2 diabetes are ongoing to test the noninferiority or superiority of gliptins (mostly compared with placebo), with prespecified, cardiovascular end points

A metabolomics study on the ischaemic heart identifies succinate as a metabolite that drives the production of reactive oxygen species and contributes to ischaemia-reperfusion injury; pharmacological inhibition of succinate accumulation ameliorates ischaemia-reperfusion injury in a mouse model of heart attack and a rat model of stroke. Succinate a heart breaker In this metabolomics study of the ischaemic heart, Michael Murphy and colleagues identify a metabolite that drives the production of reactive oxygen species and contributes to ischaemia reperfusion injury. They show that succinate is a conserved metabolic signature of ischaemia in several tissues. Succinate accumulates during ischaemia due to a reversal of the enzyme succinate dehydrogenase. Upon reperfusion the accumulated succinate is rapidly oxidized and drives reactive oxygen species production through reverse electron transport at mitochondrial complex I. Pharmacological blockade of succinate accumulation ameliorates ischaemia reperfusion injury in mouse models of heart attack and stroke. Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS) 1 , 2 , 3 , 4 , 5 . Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion 1 , 3 . Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo , while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

We previously reported that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion (vibroX) markedly improves cycling endurance capacity, increases capillary-to-fibre ratio and skeletal muscle oxidative enzyme activity in untrained young women. These findings are intriguing, since increases in oxidative muscle phenotype and endurance capacity are typically induced by endurance but not heavy resistance exercise. Here, we tested the hypothesis that vibroX activates genes associated with mitochondrial biogenesis and angiogenesis. Eight healthy, recreationally resistance-trained young men performed either vibroX or resistance exercise (RES) in a randomised, cross-over design. Needle biopsies ( M. vastus lateralis ) were obtained at rest and 3 h post-exercise. Changes in relative gene expression levels were assessed by real-time quantitative PCR. After vibroX, vascular endothelial growth factor and peroxisome proliferator-activated receptor-γ coactivator 1α mRNA abundances increased to 2- and 4.4-fold, respectively, but did not significantly change above resting values after RES. Other genes involved in mitochondrial biogenesis were not affected by either exercise modality. While vibroX increased the expression of hexokinase II, xanthine dehydrogenase, and manganese superoxide dismutase mRNA, there were no changes in these transcripts after RES. This study demonstrates that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion activates metabolic and angiogenic gene programs, which are usually activated after endurance but not resistance exercise. Thus, targeted modification of high load resistance exercise by vibration and vascular occlusion might represent a novel strategy to induce endurance-type muscle adaptations.

Introduction The clinical success of total knee arthroplasty (TKA) depends substantially on the quadriceps muscle function. A frequently applied thigh tourniquet during TKA may induce ischemia related injuries to quadriceps muscle cells. Animal limb muscles subjected to 2–5 h ischemia revealed dysfunctional mitochondria, which in turn compromised the cellular bioenergetics and increased the level of reactive oxygen species. The hypothesis of the present study was that tourniquet application during TKA for 60 min (min) affects the amount and function of mitochondria within musculus vastus medialis cells. Materials and methods In a randomized clinical trial, 10 patients enrolled to undergo primary TKA. The patients were randomly assigned to the tourniquet ( n  = 5) or non-tourniquet group ( n  = 5) after obtaining a written informed consent. For each of the groups, the first muscle biopsy was harvested immediately after performing the surgical approach and the second biopsy exactly 60 min later. All biopsies (5 × 5 × 5 mm) 125 mm 3 were harvested from musculus vastus medialis and snap-frozen in liquid nitrogen. The biochemical analysis of the prepared muscle tissues included the measurement of activities of mitochondrial respiratory chain enzyme complexes I–III and citrate synthase. Results Tourniquet-induced 60 min ischemia time did not significantly change the activities of the mitochondrial respiratory chain enzymes complexes I–III of the skeletal muscle cells. The citrate synthase activities found to be not significantly different between both groups. Conclusions The use of tourniquet during TKA within a limited time period of 60 min remained without substantial effects on the amount and function of mitochondria within human skeletal muscle cells.

Tumours are a low-oxygen environment, in this study glioblastoma cells are found to overexpress the serine hydroxymethyltransferase SHMT2; SHMT acts to reduce oxygen consumption, which confers the tumour cells with a survival advantage. Low oxygen gives tumour cells an edge Tumour cells thrive in a low-oxygen environment, and in this study David Sabatini and colleagues demonstrate a mechanism that operates in the ischaemic zone of glioblastoma cells to give tumour cells a survival advantage. Glioblastoma cells are shown to overexpress the serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC). SHMT2 favours poorly vascularized tumour cells by reducing oxygen consumption but at the same time it exposes a selective vulnerability. Glycine, the product of SHMT2 activity, if allowed to accumulate in excess within the cell can be converted into toxic molecules, hence it may be possible to target tumorigenic glioblastoma cells by inhibiting GLDC. Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment 1 , 2 , 3 . Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.

Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release . However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.

Oxidative stress caused by an imbalance in the formation and removal of reactive oxygen species (ROS) plays an important role in the development of several cardiovascular diseases. ROS originate from various cellular origins; however, the highest amount of ROS is produced by mitochondria. One of the proteins contributing to mitochondrial ROS formation is the adaptor protein p66shc, which upon cellular stresses translocates from the cytosol to the mitochondria. In the present review, we focus on the role of p66shc in longevity, in the development of cardiovascular diseases including diabetes, atherosclerosis and its risk factors, myocardial ischemia/reperfusion injury and the protection from it by ischemic preconditioning. Also, the contribution of p66shc towards cerebral pathologies and the potential of the protein as a therapeutic target for the treatment of the aforementioned diseases are discussed.

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1–3 in regulating postischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the 3 PHD isoforms in both mice and humans. Postischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. scRNA-Seq analysis of the postischemic endothelial PHD1, PHD2, and PHD3-deficient (PHD TiEC ) kidney revealed an endothelial hypoxia and glycolysis-related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed proinflammatory EC activation, reducing monocyte-EC interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions.