Inhibition of miR-25 improves cardiac contractility in the failing heart

Abstract

Heart failure is characterized by a debilitating decline in cardiac function1, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy2,3. microRNAs (miRs) are dysregulated with heart failure4,5 but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas AAV9-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 dramatically halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggests that it might be targeted therapeutically to restore function.

Inhibition of microRNA-25 by tumor necrosis factor α is critical in the modulation of vascular smooth muscle cell proliferation

“…miR-25 is known to be important in several types of cancer, including hepatocellular carcinoma, and colon, gastric and lung cancer (34)(35)(36). miR-25 has been indicated to be involved in various cellular processes, including cell proliferation, apoptosis and the release of cytokines (37)(38)(39)(40). Esposito et al (36) demonstrated that miR-25 was reduced in anaplastic thyroid carcinomas, and ectopic expression of miR-25 suppressed the proliferation and colony formation of anaplastic thyroid carcinoma cells via the induction of G 2 /M-phase cell cycle arrest (36).…”

MicroRNA in cardiovascular biology and disease

“…Anti-miR-25 delivery restores cardiac function and improves survival. 36 Also, miR-24 regulates calcium homeostasis through Junctophilin-2 repression, which results in decreased efficiency of excitation-contraction (E-C) coupling in cardiomyocytes. 37 In a recent paper, Melman et al provided evidence that increased cardiac miR-30d expression has a significant impact on responses to cardiac resynchronization therapy (CRT), and that plasma levels of miR-30d may correlate with responsiveness to CRT in heart failure patients.…”

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

“…Many pathologies have been linked to aberrant miRNA expression patterns, including cancer, metabolic disorders, heart failure and neurological diseases [10–14]. To study miRNA functioning in biological systems, potent and specific miRNA inhibitors that can be efficiently delivered in the target cell are desired.…”