Visual Abstract

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for Cu and Cu are described. L efficiently complex Cu in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, Cu is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the Cu complex to oxidation by oxygen and the Cu complex reduction by ascorbate. The affinities of L for Cu and Cu at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease.

Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischemic remodeling observed following myocardial infarction in T2D. Molidustat is an HIF stabilizer currently undergoing clinical trials for the treatment of renal anemia associated with chronic kidney disease; however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilized HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signaling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, while suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilization can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.

In type 2 diabetes (T2D), the leading cause of death is cardiovascular complications. One mechanism contributing to cardiac pathogenesis is alterations in metabolism, with the diabetic heart exhibiting increased fatty acid oxidation and reduced glucose utilisation. The processes classically thought to underlie this metabolic shift include the Randle cycle and changes to gene expression. More recently, alternative mechanisms have been proposed, most notably, changes in post-translational modification of mitochondrial proteins in the heart. This increased understanding of how metabolism is altered in the diabetic heart has highlighted new therapeutic targets, with an aim to improve cardiac function in T2D. This review focuses on metabolism in the healthy heart and how this is modified in T2D, providing evidence for the mechanisms underlying this shift. There will be emphasis on the current treatments for the heart in diabetes, alongside efforts for metabocentric pharmacological therapies.