The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent

Abstract

MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.

MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application

“…Other variables such as the use of medication or having comorbidities could also affect biomarker results or treatment efficiency. Furthermore, related to therapies, disease conditions have been shown to increase pharmacological effects of antagomiRs [ 145 ]. The disease severity and type could therefore influence therapeutic actions of miR-related therapies.…”

miR-15a/-16 Inhibit Angiogenesis by Targeting the Tie2 Coding Sequence: Therapeutic Potential of a miR-15a/16 Decoy System in Limb Ischemia

“…As an example, mRNA 3D configuration can affect the accessibility of the RISC-binding site 59 . Increasing evidence shows that binding of a miRNA to its mRNA targets can be cell type and environment dependent 60 and that this can be relevant for anti-miRNA cardiovascular therapies 61 . This was already exemplified by Eding et al., 61 who found that, upon in vivo inhibition of the cardiomyocyte-specific miR-208a, the quality and quantity of direct targets of miR-208a that are expressionally modulated depend on the presence and type of cardiac stresses, such as hypertension or myocardial infarction.…”

“…Increasing evidence shows that binding of a miRNA to its mRNA targets can be cell type and environment dependent 60 and that this can be relevant for anti-miRNA cardiovascular therapies 61 . This was already exemplified by Eding et al., 61 who found that, upon in vivo inhibition of the cardiomyocyte-specific miR-208a, the quality and quantity of direct targets of miR-208a that are expressionally modulated depend on the presence and type of cardiac stresses, such as hypertension or myocardial infarction. The anti-miR-208 treatment in healthy and diseased hearts revealed 3 subsets of targets: (1) health-specific targets, (2) disease-specific targets, and (3) targets common to health and disease.…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Thus, it was shown that silencing miR-208a expression in the hearts of Dahl salt-sensitive rats improves cardiac function [181]. The efficacy of anti-miR-208a therapy was found to be dependent on the stage of disease [182].…”