Table 1 MicroRNAs inhibiting cardiomyocyte proliferation and cardiac regeneration

miR-1

β-MHC-miR-1 transgenic mice

Overexpression of miR-1 decreases the number of cycling cardiomyocytes, results in developmental arrest at E13.5, secondary to thin-walled ventricles and heart failure.

Hand2, Ccnd1

(Zhao et al. 2005; Zhao et al. 2007; Wei et al. 2014; Gan et al. 2019)

miR-1-2^−/− mice

miR-1-2^−/− mutants display thickening of the walls of the heart, while the increased weight may be due to hyperplasia.

miR-1 dKO mice

miR-1 dKO neonatal mice display proliferating cardiomyocytes.

neonatal mouse CMs

miR-1 represses cardiomyocyte G1/S phase transition.

miR133a

miR-133a double-mutant mice

miR-133a double-mutant mice display late embryonic or neonatal lethality due to VSDs, while the surviving mutant mice display severe deficits in cardiac contractility and die from heart failure and sudden death. The absence of miR-133a expression results in ectopic expression of smooth muscle genes in the heart and aberrant cardiomyocyte proliferation.

Srf and Ccnd2

(Liu et al. 2008)

miR-15 family (miR-195, miR-15)

βMHC-miR-195 transgenic mice

Overexpression of miR-195 in the embryonic heart causes ventricular hypoplasia and ventricular septal defects.

Chek1,

Cdc2a,

Birc5,

Nusap1,

Spag5

(Porrello et al. 2011a; Hullinger et al. 2012; Porrello et al. 2013)

delivery of anti- miR-15 family (LNA- miR-15 family) to neonatal mice

Post-natal inhibition of miR-15 family induces cardiomyocyte proliferation, as well as cardiomyocytes displaying disorganized sarcomeric structures.

neonatal CMs

Inhibition of miR-15 induces cardiomyocyte viability in response to hypoxia

delivery of miR-15 anti-miRs in hearts of both mice and pigs

Inhibition of miR-15 family protectes against cardiac ischemic injury

delivery of anti- miR-15 family (LNA- miR-15 family) to neonatal mice before MI

Inhibition of the miR-15 family induces cardiomyocyte proliferation and improves left ventricular systolic function.

miR-29a

H9c2 cell line

Overexpression of miR-29a suppresses proliferation of H9c2 cell line.

CCND2

(Cao et al. 2013)

miR-99/100 and Let-7a/c

adult zebrafish

Injecting miR-99/100 mimics blocks cardiac regeneration, and injecting antagomir against miR-99/100 promots cardiomyocyte proliferation and cardiac growth

smarca5 and fntb

(Aguirre et al. 2014)

a murine model of MI

Inhibition of miR-99/100 and Let-7a/c induces the myocardial tissue to a partially dedifferentiated proliferative state after cardiac injury.

miR-101a

adult zebrafish

Inhibition of miR-101a levels at the onset of cardiac injury enhances CM proliferation, while prolonged inhibition of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue clearance.

fosab (cfos)

(Beauchemin et al. 2015)

miR-34a

delivery of miR-34a mimic to the myocardium at the time of MI

Overexpression of miR-34a inhibits functional post-MI recovery in neonatal mouse hearts.

Bcl2, Ccnd1, and Sirt1

(Yang et al. 2015)

delivery of anti-miR-34a (LNA-34a) following MI in adult mice

Inhibition of miR-34a improves cardiac function in adult hearts post-MI.

miR-128

cardiacspecific miR-128 overexpression mice

Overexpression of miR-128 impairs cardiac homeostasis, and inhibits neonatal cardiac regeneration.

Suz12

(Huang et al. 2018)

cardiac-specific miR-128 knockout mice

Inhibition of miR-128 promotes adult cardiac regeneration.

Let-7i-5p

neonatal mouse CMs

Let-7i-5p negatively regulates cardiomyocyte proliferation

Ccnd2 and E2f2

(Hu et al. 2019)

Ad-let-7i-5p/ AAV9-anti-let-7i-5p was delivered to mice

Overexpression of Let-7i-5p inhibits cardiomyocyte proliferation while inhibition of Let-7i-5p promotes cardiomyocyte proliferation.

miR-216a

neonatal mouse CMs

miR-216a negatively regulates cardiomyocyte proliferation

Jak2

(Wang et al. 2019)