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.