Sex differences in response to miRNA‐34a therapy in mouse models of cardiac disease: identification of sex‐, disease‐ and treatment‐regulated miRNAs

Abstract

MicroRNA (miRNA)-34a (miR-34a) is elevated in the diseased heart in mice and humans. Previous studies have shown that inhibiting miR-34a in male mice in settings of pathological cardiac hypertrophy or ischaemia protects the heart against progression to heart failure. Whether inhibition of miR-34a protects the female heart is unknown. Furthermore, the therapeutic potential of silencing miR-34a in settings of dilated cardiomyopathy (DCM) and atrial fibrillation (AF) has not been assessed previously. In the present study, we examined the effect of silencing miR-34a in males and females in (1) a model of moderate DCM and (2) a model of severe DCM with AF. The cardiac disease models were administered with a locked nucleic acid-modified oligonucleotide (LNA-antimiR-34a) at 6-7 weeks of age when the models display cardiac dysfunction and conduction abnormalities. Cardiac function and morphology were measured 6 weeks after treatment. In the present study, we show that inhibition of miR-34a provides more protection in the DCM model in females than males. Disease prevention in LNA-antimiR-34a treated DCM female mice was characterized by attenuated heart enlargement and lung congestion, lower expression of cardiac stress genes (B-type natriuretic peptide, collagen gene expression), less cardiac fibrosis and better cardiac function. There was no evidence of significant protection in the severe DCM and AF model in either sex. Sex- and treatment-dependent regulation of miRNAs was also identified in the diseased heart, and may explain the differential response of males and females. These studies highlight the importance of examining the impact of miRNA-based drugs in both sexes and under different disease conditions.

Therapeutic microRNA‐based strategies in cardiovascular disease discriminate sex and age difference

“…The study by Bernardo et al . () in this issue points out the need for a better understanding of microRNA expression differences in pathological tissues as correlated with sex and pathology. This may be especially important in the postmenopausal state.…”

“…Interestingly, a recent clinical study has suggested that circulating microRNAs are strongly impacted by age, sex and body mass index (Ameling et al 2015). The study by Bernardo et al (2016) in this issue points out the need for a better understanding of microRNA expression differences in pathological tissues as correlated with sex and pathology. This may be especially important in the postmenopausal state.…”

“…Thus, it is worthwhile investigating the role of micro-RNAs and their therapeutic efficacy in the context of sex differences and disease outcome. The paper by Bernardo et al published in this issue of The Journal of Physiology addressed the sex differences in response to microRNA-based therapy in a cardiac disease setting, especially the role of inhibiting miRNA-34a rather than -34b and -34c in protection against dilated cardiomyopathy (DCM) and atrial fibrillation (AF) in females and males (Bernardo et al 2016). Using transgenic mouse models administered LNA-antimiR-34a, the study demonstrated that inhibition of miR-34a provides more protection in the DCM model in females than in males, and there was no significant protection in the severe DCM and AF model in either sex.…”

Influence of sex on the number of circulating endothelial microparticles and microRNA expression in middle‐aged adults

“…Endothelial microparticles are also known to carry and transfer microRNAs (miRNA or miR) to target tissues, including endothelial cells (Bernardo et al . ). miRNAs are ∼22 nt non‐coding RNAs involved in the regulation of a number of physiological and pathophysiological processes.…”

“…; Bernardo et al . ). For example, in vitro and in vivo studies have demonstrated that lower EMP expression of miR‐126 is associated with greater atherosclerotic plaque burden in mice and a higher incidence of atherosclerotic vascular disease in middle‐aged adults (Jansen et al .…”