PMC:5003481 / 5787-9567 JSONTXT

{"project":"2_test","denotations":[{"id":"27605182-16787195-69477435","span":{"begin":341,"end":342},"obj":"16787195"},{"id":"27605182-20736237-69477436","span":{"begin":592,"end":594},"obj":"20736237"},{"id":"27605182-23248315-69477437","span":{"begin":626,"end":628},"obj":"23248315"},{"id":"27605182-17397913-69477438","span":{"begin":988,"end":990},"obj":"17397913"},{"id":"27605182-20018673-69477439","span":{"begin":1147,"end":1149},"obj":"20018673"},{"id":"27605182-17397913-69477440","span":{"begin":1541,"end":1543},"obj":"17397913"},{"id":"27605182-18694566-69477441","span":{"begin":1643,"end":1645},"obj":"18694566"},{"id":"27605182-16380711-69477442","span":{"begin":1913,"end":1915},"obj":"16380711"},{"id":"27605182-19015276-69477443","span":{"begin":1916,"end":1918},"obj":"19015276"},{"id":"27605182-20736237-69477444","span":{"begin":2096,"end":2098},"obj":"20736237"},{"id":"27605182-18957447-69477445","span":{"begin":2561,"end":2563},"obj":"18957447"},{"id":"27605182-20736237-69477446","span":{"begin":3293,"end":3295},"obj":"20736237"}],"text":"3. MicroRNAs in Cardiovascular Development\nCardiac development is a complex process in which several cell types are involved. Morphogenetic and transcriptional regulation of gene expression during cardiogenesis has been extensively investigated over the last few decades, providing a good framework to understand the formation of the heart [4]. A novel layer of complexity has been gained by the discovery of microRNAs and their pivotal role in cardiogenesis. Several studies have provided evidence of differential expression of microRNAs during heart development, both during embryogenesis [14], as well as postnatal stages [18], supporting a pivotal roles of microRNA during heart formation. Functional evidence of the role of microRNAs in the developing heart was demonstrated by selective inhibition of Dicer in a tissue-restricted manner. Conditional ablation of Dicer using Nkx2.5Cre driver mice resulted in embryonic lethality, displaying pericardial edema and cardiac hypoplasia [19]. Inhibition of Dicer function using αMHC-Cre mice also resulted in cardiac developmental impairment, and newborns die from heart failure soon after birth [20]. Whereas these studies highlight the importance of microRNA biogenesis for heart development, the role of individual microRNAs in cardiac formation remains largely unknown. However, two examples highlight the importance of microRNAs during cardiogenesis, such as germ-line deletion of miR-1-2, which resulted in ventricular septal defects and early embryonic lethality in a subset of mice [19], and germline deletion of miR-126, which resulted in embryonic lethality due to vascular leakage [21]. Curiously, targeted deletion of other abundantly expressed microRNAs in the developing heart, such as miR-133 or miR-208, have resulted in completely viable mice, suggesting a modulatory rather than a fully determinant role of these microRNAs during cardiogenesis [22,23]. In an effort to grasp the variability of microRNA expression during cardiac morphogenesis, we recently reported the dynamic expression profile during ventricular development [14]. We demonstrate that most of the differentially expressed microRNAs during ventricular maturation (55/486; 11%) displayed increased expression levels, opening a new avenue to explore the role of these microRNAs during cardiogenesis. The rapid pace of deciphering the functional roles of microRNAs has provided a cardiovascular role for 24 of these microRNAs (24/55; ~45%) (Table 1), including multiple validated targets, as nicely compiled in TarBase database [24]. In addition, a large number of microRNA microarrays have been generated in distinct cardiovascular settings, such as human cardiogenesis, embryonic stem cell- and induced pluripotent stem cell (iPS)-derived cardiomyogenesis, as well as the aging and diseased heart, enabling to trace the putative role of these differentially expressed microRNAs in other cardiovascular contexts. Thus, within this review, we will update on the functional role of these previously described differentially expressed microRNAs, and we will explore the putative functional contribution in other cardiovascular settings.\nmicroarrays-02-00081-t001_Table 1 Table 1 List of differentially expressed microRNAs during ventricular chamber development [14]. Several of them display a reported cardiovascular role (highlighted in the first column), and several validated targets have been reported, among which those with a cardiovascular role are highlighted. * MicroRNAs reported in humans (hsa-tagged), but not in mice. ** microRNAs reported in mice (mmu-tagged), but not in humans. Note that more that 85% (48/55) of the differentially expressed microRNAs are conserved in both species. iPS, pluripotent stem cell; na, not applicable.\n\n4"}