The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy

Abstract

Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload-induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

“…MiRNAs are essential to the regulation of cardiac remodeling; [3][4][5][6][7][8] however, many of them have not been well characterized. We previously demonstrated that miR-221 induces cardiomyocyte hypertrophy in vitro.…”

“…2 A large body of evidence indicates that miRNA-mediated gene regulation has important roles in the control of cardiac homeostasis and pathological remodeling. [3][4][5][6][7][8] We previously found that miR-221 is significantly upregulated in patients with hypertrophic cardiomyopathy (HCM) and in a mouse model of cardiac hypertrophy and heart failure induced by pressure overload. The in vitro overexpression of miR-221 alone is sufficient to increase the size of cardiomyocytes, accompanied by enhanced expression levels of atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP).…”

How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium

“…Thum's group elegantly showed that miRNA-212/132 inhibits autophagy in cardiomyocytes by targeting FoxO3a. Pharmacological inhibition of miR-132 reduced cardiac hypertrophy and heart failure induced by pressure overload (14). In addition, exosome-mediated miR-145 administration was found to reduce ischemic injury by activating autophagy (15).…”

Interactions between microRNAs and long non-coding RNAs in cardiac development and repair

“…Gupta et al employed an aged mice model to study the effect of anti-miR22 therapy following AMI and, compared to younger mice, old mice were shown to have higher expression levels of miR-22, a key regulator for cardiac autophagy [65]. for the cardiac hypertrophy in HF murine models [69]. Intriguingly, this study showed that, by inhibiting miR-132, the heart showed decreased cardiac fibrosis and preserved cardiac function and dilatation, eventually preventing the development of pressure overload-induced HF.…”