2.1.4 microRNAs
microRNAs (miRNAs) are small non-coding RNAs with a length of
approximately 20 to 22 nucleotides, which are widely regarded as
important post-transcriptional regulators [46]. miRNAs are involved
in regulating cell differentiation, growth, proliferation, and
apoptosis. According to the different
function or interaction of mRNA-3’
untranslated region (UTR), mature miRNAs can regulate cardiac autophagy
through mediated the expression of Atg s and hypertrophy-related
signaling pathways, which are eventually involved in the pathogenesis of
cardiac hypertrophy [47, 48].
miR-29 family is often regarded as an important regulator of cardiac
fibrosis [49]. Overexpressed miR-29a decreased autophagy activity
and promoted pathological cardiac hypertrophy via inhibiting the
expression of phosphatase and tension homolog (PTEN) and activating the
protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway
[50]. Similar to miR-29a, PTEN is also the shared target of
pro-hypertrophic miR-302 and miR-367. In Ang II-induced H9c2 cell
models, miR302-367 impaired autophagy to aggravate cardiac hypertrophy
by silencing PTEN and thus activating PI3K/Akt/mTOR pathway [51].
Hence, it is indicated that miRNAs can promote the hypertrophic growth
of cardiomyocytes by inhibiting autophagy through targeting PETN and
PI3K/Akt/mTORC1 pathways.
miR-199a is specifically expressed in cardiomyocytes and promotes the
size of cardiomyocytes [52]. In cardiomyocyte-specific miR-199a
transgenic mice, overexpressed miR-199a activated glycogen synthase
kinase 3β (GSK3β)/mTOR signaling pathway to inhibit autophagy, then
induce pathological cardiac hypertrophy [4, 53]. It has been pointed
out that knockdown of miR-199 in sponge transgenic mouse hearts
developed physiological cardiac hypertrophy with up-regulation of
peroxisome proliferator-activated receptor-gamma coactivator 1-alpha
(PGC1-α) [54]. Wu et al . showed that miR-365 can attenuate
the LC3-Ⅱ and beclin 1 expression and suppress autophagy by directly
down-regulating S-phase kinase-associated protein 2 (Skp2), thus
releasing the Skp2-mediated inhibition of mTORC1 and accelerating the
hypertrophic growth of cardiomyocytes [55, 56]. Shao et al.reported that miR-377 reduced autophagy and promoted cardiac hypertrophy
via targeting peroxisome proliferator-activated receptors γ (PPARγ) in a
TAC-mice model [57]. The miR-212/132 cluster displayed an important
function in the development of promoting pathological cardiac
hypertrophy into HF [58]. Ucar et al. reported that
overexpression of miR-212/132 down-regulated anti-hypertrophy and
pro-autophagic factor FoxO3 and over-activated hypertrophic
calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway
which significantly impaired autophagic response upon starvation in a
transgenic mice model and cardiomyocytes overexpressing miR-212/132 cell
models [59]. These miRNAs can promote the progression of cardiac
hypertrophy through regulating hypertrophy-related signaling pathways,
which also regulate autophagy.