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

MicroRNAs are a large family of small, approximately 21‐nucleotide‐long, non‐coding RNAs regulating target gene expression by repressing mRNA translation or mediating mRNA degradation. Recently, microRNAs have emerged as regulators of cell–cell communication and paracrine signalling mediators during physiological and pathological processes (Pegtel et al. 2010; Hergenreider et al. 2012), and the dysregulation of microRNAs and consequence of their target genes has been widely linked to cardiovascular disease conditions, including heart failure and cardiac hypertrophy (Thum et al. 2007; Ganesan et al. 2013). Currently, a variety of microRNAs have been identified and elucidated to play a critical role in the pathogenesis of heart failure, such as remodelling, hypertrophy, apoptosis and hypoxia, and also exhibit a dynamic and stage‐specific behaviour in the progression of heart failure. This is especially important when microRNA‐based tools are exploited as beneficial therapies for disease treatment and prevention.

Sexual dimorphism is now attracting significant attention in human diseases because sex differences in physiology and genetics can contribute to disease prevalence, severity and outcomes. It was proposed that sex steroid hormones and X‐linked genes may have considerable influence on the regulation of microRNAs resulting in a differential expression of microRNAs in males and females (Sharma & Eghbali, 2014) (see Fig. 1). Thus, it is worthwhile investigating the role of microRNAs 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. Using microRNA‐sequencing analysis, they also identified a number of microRNAs differentially expressed in the male and female DCM and AF models. These studies suggest that in the development and applications of microRNA‐based cardiac therapy one will need to consider sex differences and disease settings. Recent studies have revealed the underlying mechanisms responsible for sex differences in microRNA expression. Sex‐specific signals may be mediated by oestrogen, androgen and oestradiol as well as other sex hormones, which are functionally relevant in male and female cardiovascular cells, and also contribute to the differential expression of microRNAs (Klinge, 2009; Li et al. 2014). In addition, ageing is a risk factor for cardiovascular diseases and increasing evidence suggests that microRNAs are involved in cardiovascular ageing, and the alteration of microRNA expression during ageing can exacerbate or attenuate cardiovascular dysfunction and senescence. One of the superstars of microRNAs, microRNA‐34a, has been suggested to be a risk factor in cardiac ageing (Chiao, 2013; Seeger & Boon, 2016), and was shown to be significantly increased in the aged heart contributing to age‐associated cardiomyocyte cell death. Importantly, microRNA‐34a inhibition reduced cell death and fibrosis following acute myocardial infarction and improved the recovery after myocardial infarction (Boon et al. 2013). Previous studies have also demonstrated that the incidence and progression of heart disease is remarkably higher in men than in age‐matched women before menopause, whereas after menopause the incidence is similar or even higher in women than age‐matched men (Barrett‐Connor, 1997; Crabbe et al. 2003), thus, microRNA‐based therapy will have to take ageing into account in addition to sex difference and disease state.

Figure 1. A schematic illustration showing the potential mechanisms for sex differences in microRNA expression (Panels A and B) .

ERα: oestrogen receptor α; AR: androgen receptor; F: female; M: male; X: X chromosome; Y: Y chromosome. Adapted from Sharma & Eghbali (2014).

Recently, microRNAs detected in the circulation are attracting more and more attention, and have been proposed as potential diagnostic, prognostic biomarkers and as biomarkers for the response to therapy in cardiovascular diseases. 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. These data will provide valuable biomarkers for the prognosis, diagnosis and response to therapy in cardiovascular diseases, and will be helpful for developing efficient microRNA‐based therapies specifically tailored to male and female patients.

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Competing interests

None declared.