Table 1.

Major animal studies demonstrating EV cardioprotection and the potential underlying mechanisms of action.

Study	EV source	Animal model	Ml model	Cardioprotective effects	Mechanism
(Timmers et al., 2007)	MSC	Pig	IRI	Improved cardiac function Reduced infarct size Reduced oxidative stress	Proteins, which reduced phosphorylation of SMAD2, which deregulated TGF-β signaling. Inhibition of caspase 3 activity.
(Timmers et al., 2011)	MSC	Pig	Permanent ligation	Improved cardiac function Reduced infarct size Increased capillary density Decreased collagen density
(Arslan et al., 2013)	MSC	Mouse	IRI	Improved cardiac function Reduced infarct size Reduced immune infiltration	Proteins which upregulated PI3K/AKT pathway Proteins which reduce activation of c-JNK.
(Fang et al., 2014)	IPC MSC	Mouse	Permanent ligation	Improved cardiac function Reduced apoptosis in CM Reduced fibrosis	miR-22
(Teng et al., 2015)	MSC	Rat	Permanent ligation	Improved cardiac function Reduced infarct size Reduced fibrosis Reduced immune infiltration Increased angiogenesis
(Kang et al., 2015)	CXCR4 MSC	Rat	Permanent ligation	Improved cardiac function Reduced infarct size Increased angiogenesis	Upregulation of PI3K/AKT pathway Inhibition of caspase 3 activity
(Yu et al., 2015)	GATA-4 MSC	Rat	Permanent ligation	Improved cardiac function Reduced infarct size Reduced apoptosis in CM	miR-19 Upregulation of PI3K/AKT pathway
(Liu et al., 2017)	MSC	Rat	IRI	Improved cardiac function Reduced infarct size Increase in autophagy	Upregulation of Akt/mTOR and AMPK/mTOR pathways
(Zhu et al., 2018b)	Hypoxic MSC	Mouse	Permanent ligation	Improved cardiac function Reduced infarct size	miR-125b-5p
(Zhu et al., 2018a)	Hypoxic MSC	Mouse	Permanent ligation	Improved cardiac function Reduced infarct size Reduced apoptosis in CM Increased angiogenesis	miR-210
(Barile et al., 2014)	CPC	Rat	Permanent ligation	Improved cardiac function Increased angiogenesis Inhibit CM apoptosis Reduce infarct size	miR-132
(Gray et al., 2015)	Hypoxic CPC	Rat	IRI	Improved cardiac function Reduce fibrosis	miR-17,−199a, −210, 292
(Ibrahim et al., 2014)	CDC	Mouse	Permanent ligation	Improved cardiac function Promoted cell survival Reduce infarct size	miR-14a, −22, −24
(de Couto et al., 2017)	CDC	Rat, Pig	IRI	Improved cardiac function Reduced infarct size Reduced infiltration of CD68+ Mϕ	miR-14a, −181b, −126

Table 1. Mesenchymal stromal cell, MSC; cardiac progenitor cell, CPC; cardiosphere derived cells, CDC; ischemic preconditioning, IPC; ischemia/reperfusion injury, IRI; Cardiomyocyte, CM; Chemokine receptor 4, CXCR4; Macrophage, Mφ; Micro RNA, miR.