Schroen and Heymans MicroRNAs in Hypertensive Heart Disease 1191

In recent years, microRNAs (miRs) have caused a true revolution in the cardiovascular research field. miRs are a class of highly conserved, small noncoding RNAs. They are transcribed from “normal” genes, and their precursor transcripts are enzymatically processed to a mature and active form by Drosha/Dgcr8 and Dicer enzyme complexes.1–3 miRs fine tune the expression of 30% to 50% of the protein-coding genes by binding to partly complementary base pairs in 3 untranslated regions (UTRs) of mRNAs and thereby interfering with translation; targeted mRNAs are either degraded or temporarily silenced.4,5 In this way, miRs add another level of complexity to the highly regulated eukaryotic interactome, and their actions (partly) explain why mRNA expression so often does not agree with protein expression levels. So far, 700 human and 500 mouse miR genes have been included in the miRBase (www.microrna.sanger.ac.uk), the primary source of miR data, and computational analyses predict that these numbers will increase.6 The complexity of miR regulation of protein expression is illustrated by the fact that several miRs can target 1 gene, whereas several genes can be targeted by 1 miR.5,7 Bioinformatical tools to predict gene targets of a given miR exist, and their accuracy increases. Identifying the relevant miRtargeted genes and building new miR-gene networks is a challenge that lies ahead of us. The expression of miRs is tightly controlled and highly tissue, developmental stage, and disease specific. The heart expresses 2 unique miR families under the control of cardiogenic transcription factors like the serum response factor and myocyte enhancer factor 2: miR-1 and miR-133a (Figure 1 and please see the online Data Supplement at http://hyper. ahajournals.org for Table S1). 8–11 miRs -1-1 and -1-2 represent 40% of all of the expressed miRs in the heart12 and are encoded from bicistronic units together with the 2 members of the miR-133a subfamily.13,14 Another family unique to the heart is composed of miRs 208a and 208b, which lie within and are encoded together with the cardiac-restricted and -myosin heavy chain (MHC) genes, respectively.15,16 miRs are of crucial importance to the heart to develop and function properly. In mice, deletion of all of the cardiac miRs by cardiomyocyte Dgcr8 or Dicer knockout is not tolerated,12,17,18 and also the specific deletion of cardiac miRs 1 or 133 leads to (partial) embryonic lethality and heart failure (please see Table S1). 8,14,18–20 From 2001 until now, several studies have investigated miR expression in the healthy heart,21–24 during pressure overload in mice and rats25–32 and in different etiologies of human heart failure,28,33–37 as reviewed previously38 and now updated with the latest studies (please see Figure S1). miRs that consistently come to attention are let-7b and miR-15b, -21, -23a, -27b, -103, -125b, -140*, -195, -199a, and -214, which are upregulated in all of the cardiac pathologies studied, as well as miR-30e, -150, -185, and -422b, which are all downregulated during hypertensive heart diseases. Still, the identification of miRs involved in cardiac development and pathology and knowledge on their biological function is exceedingly incomplete, offering an exciting challenge to cardiovascular researchers. Therefore, miRs currently seem to be the most popular kid in the cardiovascular research school.