Regulation of SIRT1 by Oxidative Stress-Responsive miRNAs and a Systematic Approach to Identify Its Role in the Endothelium

Significance: Oxidative stress is a common denominator of various risk factors contributing to endothelial dysfunction and vascular diseases. Accumulated evidence suggests that sirtuin 1 (SIRT1) expression and/or activity is impaired by supraphysiological levels of oxidative stress, which in turn disrupts endothelial homeostasis. Recent Advances: Several microRNAs (miRNAs) are induced by oxidative stress and termed as oxidative stress-responsive miRNAs. They may play a role linking the imbalanced redox state with dysregulated SIRT1. Critical Issues: This review summarizes recent findings on oxidative stress-responsive miRNAs and their involvement in SIRT1 regulation. Because of the unique characteristics of miRNAs, research in this new area requires an integrative approach that combines bioinformatics and experimental validation. Thus, a research strategy is discussed to identify the SIRT1-regulating miRNAs under oxidative stress and their functional outcomes in relation to endothelial dysfunction. Additionally, the miRNAs implicated in vascular diseases such as atherosclerosis and abdominal aortic aneurysms are discussed along with the translational potential and challenges of using miRNAs and its analogs as therapeutic agents. Future Directions: Although at its infancy, research on oxidative stress-responsive miRNAs and their regulation of SIRT1 may provide new insights in understanding vascular disorders. Moreover, systematic approaches integrating in silico, in vitro, and in vivo observations can be useful tools in revealing the pathways modulating endothelial biology. Antioxid. Redox Signal. 19, 1522-1538.