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Review
. 2014 Sep;143(3):305-15.
doi: 10.1016/j.pharmthera.2014.03.009. Epub 2014 Apr 1.

Stromal derived factor 1α: a chemokine that delivers a two-pronged defence of the myocardium

Daniel I Bromage  1 , Sean M Davidson  1 , Derek M Yellon  1
Affiliations
Review

Stromal derived factor 1α: a chemokine that delivers a two-pronged defence of the myocardium

Daniel I Bromage et al. Pharmacol Ther. 2014 Sep.

Abstract

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia-reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia-reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a 'two-pronged' defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting.

Keywords: AMI; CXCR4; Cardioprotection; DPP-4; Ischemic conditioning; SDF.

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Figures

Fig. 1
Fig. 1
The SDF-1–CXCR4 signalling axis. Remote preconditioning may enable both acute and chronic cardioprotective pathways (see text for details). SDF-1α, stromal derived factor-1α; HIF-1α, hypoxic inducible factor-1α; ADRCs, adipose tissue derived regenerative cells; BMSCs, bone marrow stem cells (including mesenchymal stem cells, hamatopoietic stem cells and endothelial stem cells); ECSCs, endogenous cardiac stem cells; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphoinositide 3 kinase; MEK1/2, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinases; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; mPKC, mitochondrial protein kinase C; mKATP, mitochondrial ATP-sensitive potassium channel; ROS, reactive oxygen species; MPTP, mitochondrial permeability transition pore.
Fig. 2
Fig. 2
SDF-1α prior to ischaemia improves contractile recovery of rat heart papillary muscle that is isolated and subject to 30 min hypoxia and 2 h reoxygenation. Before hypoxia, the rat papillary muscle was perfused with 1) SDF-1 for 10 min; or 2) AMD3100 for 5 min then AMD3100 plus SDF-1 for 10 min, or 3) AMD3100 alone for 15 min. Control papillary muscle was untreated. Data expressed as mean ± SE. The functional recovery of muscle treated with SDF-1 alone was significantly improved (P < 0.05) (Davidson et al., 2013).
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