title: Remote ischaemic preconditioning involves signalling through the SDF-1α/CXCR4 signalling axis.
abstract: Ischaemic preconditioning is one of the most potent experimental modalities known to decrease infarct size after ischaemia and reperfusion. Much interest has been stimulated by the phenomenon of remote ischaemic conditioning (RIC), in which the preconditioning stimulus is applied to a limb remote from the heart to stimulate cardioprotection via an unidentified humoral factor, believed to be a protein between 3.5 and 15 kDa. Stromal cell-derived factor-1 (SDF-1α or CXCL12) is a chemokine of 10 kDa that is induced by hypoxia and recruits stem cells, but also exerts direct, acute, cardioprotection via its receptor, CXCR4. The serum dipeptidase DPPIV cleaves and inactivates SDF-1α. We measured SDF-1α in rat plasma and found it was significantly increased by RIC. DPPIV activity was unchanged after RIC, suggesting that increased synthesis or release or SDF-1α caused the increase in plasma levels. AMD3100, a highly specific inhibitor of CXCR4, was used to investigate the hypothesis that SDF-1α is involved in RIC. RIC in rats, which decreased infarct size from 53 ± 3 % to 27 ± 3 % (n = 6, P < 0.05), was blocked in rats treated with AMD3100 (40 ± 4 %). RIC also improved functional recovery of cardiac papillary muscle, and this, too, was blocked by AMD3100. Direct application of SDF-1α was confirmed to be protective in this model and was blocked by AMD3100. RIC stimulates SDF-1α release, and this 10-kDa peptide appears to be required for the mechanism of RIC.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Pradeep
authors.initials: P
authors.lastname: Selvaraj
authors.forename: David
authors.initials: D
authors.lastname: He
authors.forename: Claire
authors.initials: C
authors.lastname: Boi-Doku
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yellon
authors.forename: Jose M
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4