Table 3.

Exosomes released in response to RIC in recent human/animal studies

Authors	Treatment group	Exosome content/pathways	Inflammatory/therapeutic action
Haller et al. (RCT) [45]	N = 32 patients with STEMI undergoing forearm RIC prior to PCI vs controls PCI alone	Platelet-derived EV’s (Calcein/AM+/CD41+) Endothelial-derived EV’s Leucocyte derived EV’s (CD14, CD66b)	Pro-thrombotic—no differences observed between RIC vs controls ? Pro/anti- inflammatory – monocyte derived micro-particles elevated in RIC group at 1-month post STEMI, otherwise no differences observed
Cui et al. [20]	SH-SY5Y neuronal cells incubated with venous serum of healthy male volunteers following forearm RIC	mi-RNA-126	Increased tolerance to oxygen/glucose deprivation via downregulation of DNMT3B
Chen et al. [16]	Rats undergoing bilateral hind limb RIC prior to LAD occlusion donated plasma to recipient animals in a model of myocardial infarction, and to CMVECs in an in vitro H/R model	HSP70/HIF-1α/eNOS/iNOS/ANG-1/VEGF	Improvement in LVEF in vivo Increase in angiogenesis and reduction in apoptosis in vitro
Li et al. [91]	Mice undergoing bilateral hind limb RIC donated plasma exosomes to recipient mice pre- dMCAO	HIF-1α	Reduction in cerebral infarct size
Pan et al. [110]	Mice undergoing RIC by bilateral femoral artery clamping 24 h prior to caecal puncture, donated plasma to recipient mice with LPS challenge	mi-R21/HIF-1α	Improvement in survival Reduced plasma creatinine levels Reduced serum IL-6, TNF-α which was abrogated in mi-R21 knock-out mice
Minghua et al. [103]	Rats undergoing bilateral hind limb RIC prior to LAD occlusion, donated plasma to H9c2 cells in vitro and to recipient animals in vivo	mi-R24/Bim	Reduced apoptosis and caspase-3 in vitro Reduced infarct size in vivo
Frey et al. (RCT) [35]	n = 58 patients with IHD underwent left arm RIC prior to and during isoflurane/sufentanil anaesthesia for CABG, exosomes were sampled and analysed at up to 1 hr post induction	mi-R21, mi-R28, mi-R320, mi-R92a	Reduction in post-operative troponin; however, not known whether related directly to mi-R21
Wider et al. [144]	Both normoglycemic and diabetic rats underwent bilateral limb RIC prior to LAD occlusion and reperfusion. Plasma was donated and incubated with HL-1 cardiomyocytes exposed to H/R	? Apo lipoprotein B-100; C4 complement (multiple proteins identified)	Reduced apoptosis in vitro The above attenuated in diabetic rats

STEMI ST-elevation myocardial infarction, PCI percutaneous coronary intervention, EV extracellular vesicles, LPS lipopolysaccharide, dMCAO distal middle cerebral artery occlusion, I/Rischaemia/reperfusion, LAD left anterior descending, H/R hypoxia/reoxygenation, HIF-1α hypoxia inducible factor 1 alpha, HSP70 heat shock protein 70, eNOS endothelial nitric oxide synthase, VEGF vascular endothelial growth factor, ANG-1 angiopoietin 1, LVEF left ventricular ejection fraction, CABG coronary artery bypass graft, IHD ischaemic heart disease