Secreted frizzled protein 3 is a novel cardioprotective mechanism unique to the clinically relevant fourth window of ischemic preconditioning

Most studies on ischemic preconditioning (IPC) use one or two ischemic stimuli before examining cardioprotection. To better simulate the clinical situation, we examined, in pigs, the effects of six episodes of 10 min coronary artery occlusion (CAO) 12 h apart, followed by 60 min CAO. We named this model the fourth window of IPC. To determine the novel mechanisms mediating cardioprotection in the fourth window, gene analysis was examined in fourth window IPC cardiac tissue 60 min after the last episode of 10 min CAO. Secreted frizzled-related protein 3 (sFRP3) was the most significantly upregulated gene that was unique to the fourth window, that is, not found in the first, second, or third window IPC. To study the effects of sFRP3 on cardioprotection, sFRP3 was injected in the hearts of wild-type (WT) mice. In the [CAO/coronary artery reperfusion (CAR)] model (30 min CAO followed by 24 h CAR), infarct size was less, P < 0.01, after sFRP3 injection (14% ± 1.7%) compared with vehicle injection (48% ± 1.6%). sFRP3 injection also protected the development of heart failure following permanent CAO for 2 wk. Left ventricular ejection fraction was significantly improved, P < 0.05, at 2 wk after CAO with sFRP3 (53% ± 5%) compared with vehicle (36% ± 2%) and was accompanied by significant, P < 0.01, reductions in myocardial fibrosis (53% ± 4%), myocyte size (17% ± 3%), apoptosis (100%), and mortality (56%). Thus, sFRP3, unique to the clinically relevant fourth window IPC model, is a novel mechanism mediating ischemic cardioprotection. NEW & NOTEWORTHY 1) This investigation identifies the novel fourth window of ischemic preconditioning. 2) sFRP3 was identified as the most significantly upregulated gene in the fourth window and was shown to induce cardioprotection when administered to the hearts of wild-type mice.