Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy

Abstract

Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia–reperfusion injury and cardioprotection by ischaemic conditioning protocols

“…Clinical trials evaluating the overall cardiovascular risks and benefits after administration of dipeptidyl peptidase-4 inhibitors have shown that hospitalisation for heart failure was increased in saxagliptin-treated patients (Scirica et al, 2013), whereas the rates of major adverse cardiovascular events were not increased with the alogliptin and sitagliptin as compared with placebo (Green et al, 2015;White et al, 2013). Nevertheless, the relationship between dipeptidyl peptidase-4 inhibitors and heart failure is complex (reviewed in Ziff, Bromage, Yellon, & Davidson, 2018).…”

Circulating blood cells and extracellular vesicles in acute cardioprotection

“…For example, they are a major source of CXCL12 (stromal cell derived factor-1a, SDF-1a), which is released upon activation and can reduce IR injury in rodent and human myocardium, in addition to promoting longer time-scale repair mechanisms. 16,17 Platelet-derived S1P appears to make an important contribution to protection from IR injury. Platelets contain sphingosine kinase, which can transform membrane sphingosine into S1P for storage and release.…”

Exosomes and cardioprotection – A critical analysis

“…overexpressed CXCR4 in MSC cells, since this receptor for SDF-1α is important in homing and targeting of stem cells ( Bromage et al., 2014 , Ziff et al., 2017 ). Furthermore, activation of the CXCR4-SDF-1α pathway can protect the heart from IR injury, and may be important for the suppression of heart failure ( Sluijter et al., 2017 , Davidson et al., 2013 , Bromage et al., 2014 , Ziff et al., 2017 , Malik et al., 2015 ). Exosomes released by MSC-CXCR4 cells were found to significantly upregulate levels of IGF-1α and pAkt in cardiomyocytes, as well as enhancing VEGF expression and vessel formation in vitro ( Kang et al., 2015 ).…”