Long noncoding RNAs in diabetic retinopathy.

W ith the advent of next generation sequencing technologies it became evident that the majority of the human genome is transcribed, whereas only 1.5% to 2% of the ge-nome encode proteins. 1 The remaining transcripts are referred to as noncoding RNAs. With respect to microvascular dys-function, functional roles of noncoding RNAs are in particular evident for microRNAs (miRNAs, miRs), 2 which belong to the group of small noncoding RNAs (<200 nt). In contrast, the contribution of long noncoding RNAs (lncRNAs; >200 nt) is not conclusively defined. Even though the particular functions of lncRNAs seem to be diverse, their mechanisms of action can be grouped into 3 main themes. 3 Hence, lncRNAs can (1) function as decoys for proteins or RNAs, (2) serve as scaffolds for higher order complexes, or (3) act as molecular guides to ensure the proper localization of their binding partners. Taking these central functions into account, which finally encompass the fields of transcriptional and post-transcriptional regulation, as well as subcellular dynamics, dysregulation of lncRNA expression is often associated with complex human diseases. 4 In the field of vascular biology, the importance of lncRNAs in cellular homeostasis was recently uncovered by the finding that the lncRNA MALAT1 was identified to be crucial for the angiogenic response of endothelial cells as well as for vascularization in vivo. In this issue of Circulation Research, Yan et al 6 revealed a regulatory role of the lncRNA myocardial infarction–associ-ated transcript (MIAT) in diabetes mellitus–induced micro-vascular dysfunction. MIAT (which is also known as RNCR2, AK028326, or Gomafu) was first identified as susceptible lo-cus for myocardial infarction 7 and was reported to be highly expressed in retinal precursor cells. 8 Manipulation of MIAT triggers pleiotropic effects on brain development, which are at least in part mediated by aberrant splicing of Wnt7b. 9 Yan et al 6 now show that MIAT is strongly upregulated in the retinas of diabetic rats and patients. Consistently, high glucose conditions trigger upregulation of MIAT in vitro. In turn, interference with MIAT expression was found to improve visual functions under diabetic conditions along with beneficial effects for reti-nal vessel impairment. In particular, MIAT knockdown in vivo was shown to be accompanied by reduced vascular leakage and by counteracting the diabetes mellitus–induced upregula-tion of proinflammatory proteins, thereby alleviating retinal vessel impairment (Figure). The mechanisms underlying these impressive therapeutic benefits are not entirely clear. Because endothelial cells are considered as primary cellular …