REVIEW Application of microRNAs in diagnosis and treatment of cardiovascular disease A. Wronska, 1 I. Kurkowska-Jastrzebska 2,3 and G. Santulli 1 1 Helen and Clyde Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY, USA 2 Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland 3 2nd Department of Neurology, National Institute of Psychiatry and Neurology, Warsaw, Poland Received 8 September 2014, revision requested 8 October 2014, revision received 20 October 2014, accepted 24 October 2014 Correspondence: Anetta Wronska, Department of Physiology and Cellular Biophysics, Columbia University, 1150 St Nicholas Ave, Russ Berrie Science Pavilion 515, New York, NY 10032, USA. E-mail: aew2116@columbia.edu Abstract Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Innovative, more stringent diagnostic and prognostic biomar- kers and effective treatment options are needed to lessen its burden. In recent years, microRNAs have emerged as master regulators of gene expression – they bind to complementary sequences within the mRNAs of their target genes and inhibit their expression by either mRNA degradation or translational repression. microRNAs have been implicated in all major cellular processes, including cell cycle, differentiation and metabolism. Their unique mode of action, fine-tuning gene expression rather than turn- ing genes on/off, and their ability to simultaneously regulate multiple ele- ments of relevant pathways makes them enticing potential biomarkers and therapeutic targets. Indeed, cardiovascular patients have specific patterns of circulating microRNA levels, often early in the disease process. This article provides a systematic overview of the role of microRNAs in the pathophysiology, diagnosis and treatment of CVD. Keywords atherosclerosis, biomarkers, cardiovascular disease, microRNA. Cardiovascular disease (CVD) is the most frequent cause of mortality and morbidity worldwide. It is esti- mated that almost half of CVD mortality can be attributed to coronary heart disease (CHD). microRNAs (miRNAs) are short (17–25 nucleotides long) single-stranded RNA molecules. In recent years, they have emerged as ubiquitous regulators of a pleth- ora of physiological and pathophysiological processes in cells. Numerous studies have implicated miRNAs in cardiovascular physiology, as well as in the initiation and progression of CVD [reviewed in (Vickers et al. 2014, Xin et al. 2013c, van Rooij & Olson 2012, Ono et al. 2011)]. miRNA biology and preclinical studies First discovered in C. elegans in 1993 (Lee et al. 1993), miRNAs downregulate their target genes through mRNA degradation or translational repres- sion. miRNA genes are transcribed in the nucleus by RNA polymerase II as long primary transcripts (pri- miRNAs), which may contain more than one miRNA (Figure 1). Pri-miRNAs are processed by the RNAse III enzyme (Drosha) into hairpin-like pre-miRNAs, which are exported into the cytosol by exportin-5. Once in the cytosol, pre-miRNAs are processed by RNAse III (Dicer) to mature miRNAs, which can then © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12416 60 Acta Physiol 2015, 213, 60–83