MicroRNAs are short noncoding 18-25 nucleotide long RNA which bind and inhibit mRNA. Currently, there are over 1000 known human microRNAs, and microRNAs control over 50% of mammalian protein coding genes. As more is learnt about the regulation and wide reaching function of microRNA, their importance in regulating cell pathways in homeostasis and disease are becoming more apparent. As with other tissues, microRNAs have been identified to play important roles in heart development, homeostasis, exercise induced hypertrophy, and disease. During development, several microRNA have been shown to be upregulated during specific points, such as miR-1, miR-133 and miR-15 which all play important roles in ventricular cardiomyocyte expansion. MicroRNA have also been found to play important roles in exercise induced changes in the heart, such as miR-222 which is upregulated during exercise and has also been found to be protective against ischemia reperfusion in the mouse. In both human and animal studies many microRNA have been shown to be regulated during disease in the heart, and in animal studies reversal of disease can be seen when these microRNA are reverted back to baseline levels. For example the cardiac specific miR-208a is upregulated during pathological cardiac hypertrophy in mice after thoracic aortic banding. When miR-208a knockout mice were banded there was no hypertrophy or fibrosis observed demonstrating that increased miR-208a leads to increased hypertrophy in the mouse heart after thoracic aortic banding.
MicroRNA are stable in plasma, and research into circulating microRNA is a fast growing area as they may be used as biomarkers to identify patients with damaged or failing hearts. MicroRNA can enter the circulation by either leaking out from damaged tissue or from secretion from tissue by extracellular vesicles. Specific groups of microRNAs have been identified in the plasma which corresponds to myocardial infarction, atherosclerosis, type two diabetes and heart failure. For example, miR-1, miR-133a and miR-208a were identified in plasma within 4 hours of myocardial infarction, compared to healthy controls (reviewed in Creemers et al, Circulation Research 2012 110;483-495). These microRNA levels peaked before troponin I, the classic marker for myocardial infarction and heart damage, and may be useful for identifying patients with myocardial infarction at earlier time points. Research is also being carried out to investigate where circulating microRNA that originate in the heart go, and whether they are involved in cell-cell and organ-organ communication in disease.
As with other types of small RNA, microRNA have the potential for long lasting therapeutic targeting, either through addition of microRNA mimics to replace down regulated microRNA, or through inhibition of increased endogenous mircoRNA through microRNA antagomers, locked nucleic acid, or microRNA sponges. Several areas of concern in developing microRNA as therapeutics include; development of safe and efficacious delivery of microRNA to target tissue, and potential off target effects, as microRNA often target large signaling pathways and multiple targets through their seed region. Much work is being carried out on both of these areas to develop techniques to target the heart specifically and to produce large scale assays which allow determination of potential off target effects.
Overall, as the field of cardiac microRNA continues to grow, more opportunities for understanding and detecting heart disease will emerge, leading to an increased ability to identify and treat patients with cardiac dysfunction.
About the Author
Bridget Simonson is a post-doctoral fellow at the Cardiology department at the Beth Israel Deaconess Medical Centre. I would like to give her a big thank you for her providing her time to produce this article!