Table 1.

A list of microRNAs which can impair PI3K/Akt signal activity and potential mechanisms of their impact on ischemia–reperfusion injury and post-infarction remodeling.

miRNA	DM2	Ref.	The Potential Regulatory Mechanism
miR-19	-	-	MiR-19a protects H9C2 cardiomyocytes against H/R-induced apoptosis by inhibiting PTEN [292]; MiR-19b promotes NRCFs proliferation and migration by targeting PTEN [293].
miR-21	up *	[294,295,296,297]	Targets PTEN expression and promotes adverse ventricular remodeling by induction of MMP-2 in cardiac fibroblasts [269], alleviates cardiomyocytes apoptosis and reduces infarct size through decreasing Bax/Bcl-2 ratio and caspase-3 expression [271], decreases cardiomyocytes autophagy [273].
miR-34	up	[294]	Inhibition of miR-34a attenuates MI-induced LV remodeling in mice and induces Akt phosphorylation [298]; activates PI3K/AKT pathways via up-regulating ZEB1 in cardiomyocytes and attenuates hypoxia-induced injury [299]; protects H9C2 cardiomyocytes from high-glucose-induced injury [300].
miR-122	up	[295,301]	Aggravates oxygen–glucose deprivation and reperfusion apoptosis of H9C2 cardiomyocytes inhibiting AKT/GSK-3β/β-catenin and AKT/mTOR pathway signaling [302,303];
miR-126	down	[295,304,305,306,307,308]	Targets PIK3R2 and SPRED1 expression, resulting in elevated activity of the PI3K/Akt signal and improved angiogenesis, left ventricle function after MI, and alleviated apoptosis of both endothelial cells and cardiomyocytes [278,279,280,281,282,283,284]
miR-130	up	[295,309,310]	Attenuates LV dysfunction and remodeling after MI targeting PTEN and increasing activity of Akt [311]
miR-145	down	[312]	Inhibits cardiac cells apoptosis and ROC activity by enhancing the PI3K/Akt and SGK1 activity [285], promotes autophagy and reduces myocardial infarct size targeting FRS2 and inducing PI3K/Akt/mTOR activity [286,287], attenuates fibrosis via activation of the Akt/CREB and suppression of the AKT/GSK-3β/β-catenin pathways [288,289].
miR-155	up	[313,314]	Targets IKKi expression decreasing its cardioprotective role in activating Akt and NF-κB, independent of the PI3K, and enhances cardiac hypertrophy [315], inhibits the AKT/CREB pathway signal and impairs the left ventricle function [316].
miR-223	up	[310,317,318]	Inhibits angiogenic function of CMECs by decreasing the PI3K/Akt signal activity [319], regulates cardiac hypertrophy by modulating the p-Akt activation [320], and mediates cardiac fibrosis after MI targeting RASA1 expression, which promotes MEK1/2, ERK1/2 and AKT phosphorylation [321].
miR-320	up	[295,306]	Increases vulnerability of cardiomyocytes to hypoxia/reoxygenation injury targeting expression of Akt3 [322].
miR-375	up	[323,324]	Exacerbates inflammation and cardiomyocyte apoptosis, decreases angiogenesis and impairs the LV function after MI by a reduction in PDK-1 expression, which results in decreased Akt Thr-308 phosphorylation [325,326].

(DM—diabetes mellitus, *—indicates a contradictory finding where the miRNA was found to be down-regulated in at least one study). Akt—protein kinase B, Bax—Bcl-2-associated X protein, Bcl-2—B-cell lymphoma 2, CMECs—cardiac microvascular endothelial cells, CREB—cAMP response element-binding protein, ERK1/2—extracellular signal-regulated kinase1/2, FRS2—fibroblast growth factor receptor substrate 2, GSK-3β—glycogen synthase kinase 3 β, LV—left ventricle, MEK1/2—mitogen-activated protein kinase kinase1/2, MI—myocardial infarction, MMP-2—metalloproteinase 2, mTOR—mammalian target of rapamycin, NF-κB—nuclear factor κ-light-chain-enhancer of activated B cells, NRCFs—neonatal rat cardiac fibroblasts, IKKi—inducible IkB kinase, H/R—hypoxia/reoxigenation, p-Akt—phosphorylated Akt, PDK-1—phosphoinositide-dependent kinase-1, PI3K—phosphoinositide 3-kinase, PIK3R2—phosphoinositide 3-kinase regulatory subunit 2, PTEN—phosphatase and tensin homolog, RASA1—Ras p21 protein activator 1, ROC—Ras of complex proteins, SGK1—serum and glucocorticoid-regulated kinase 1, SPRED1—Sprouty-related EVH1 domain containing 1, Thr-308—threonine 308, ZEB1—zinc finger E-box binding homeobox 1.