Circulating MicroRNAs Link Inflammation to Impaired Wound Healing in Diabetes.

S oon after their discovery in 1993, it became clear that microRNAs (miRs) regulate virtually all cellular processes. 1 Since then, many miRs have been described to coordinate gene expression programs in the context of cardiovascular disease, including diabetes mellitus. 2,3 MiRs usually perform their duties intracellularly, but interest in extracellular miRs as biomarkers or intercellular messengers has risen recently. In the cardiovascular system, it has been shown that miRs can travel between endothelial cells, smooth muscle cells, cardiac fibroblasts, and cardiomyocytes, thereby affecting gene expression in recipient cells. 6–8 Next to their role in intercellular communication , circulating miRs were also shown to be powerful biomarkers for various cardiovascular conditions. In this issue of ATVB, Dangwal et al 12 show that miR-191 is both a circulating biomarker for type-2 diabetes mellitus and an inter-cellular messenger with a potent effect on wound healing. Using miR microarrays, the authors were able to identify several miRs that are differentially detectable in the plasma of patients with type-2 diabetes mellitus compared with healthy controls. 12 These miRs include miR-191 and miR-200b. Interestingly, the reduction of miR-191 in plasma of patients with type-2 diabetes mellitus was also seen by Zampetaki et al. 11 However, Dangwal et al 12 also noticed that the presence of chronic wounds essentially reversed the extracellular levels of miR-191 in the circulation. Rather than dismissing this seemingly contradictory finding, the authors set out to investigate the meaning of this observation. What the groups of Tschoepe and Thum found is that inflammatory stimuli that are present in wound fluid induce the secretion of miR-191 by endothelial cells. 12 This finding could explain the observation that miR-191 increases in type-2 diabetes mellitus patients with wound healing complications, compared with type-2 diabetes mellitus patients without wounds. The authors then went on and tested whether miR-191 may have a functional effect in endothelial cells and der-mal fibroblasts that would potentially show a role of miR-191 in wound healing in diabetic conditions. Indeed, this was the case because the authors showed that secreted miR-191 can be taken up by other endothelial cells and dermal fibroblasts. In recipient cells, miR-191 impaired angiogenesis, migration, and apoptosis by targeting the tight junction protein ZO-1 (Figure 1). Because ZO-1 has been shown to be essential for migration, 13 miR-191-mediated downregulation could very well explain the migration and angiogenesis defects observed after overexpression of miR-191. As all miRs are capable …