Age‐related changes in circulating microRNA profile and brain endothelial microvascular cell response to oxidative insult

The possible implication of various microRNAs (miRNAs) in the manifestation of brain aging and neurodegenerative disorders has been the subject of multiple studies. In contrast, the impact of miRNAs on the cerebral microvasculature during aging remains elusive. Although impaired cerebral microcirculation and endothelial cell dysfunction have been described in the aging brain, the mechanisms promoting this impairment are still unclear. We hypothesized that a change in circulating miRNA profile with age might affect brain microvascular endothelial cells (BMVECs) function. In order to test this hypothesis, we first tested 4‐, 12‐ and 20‐month old Fisher344 rats in a Morris Water Maze test. Results showed that compared to younger groups, 20‐month old rats showed a significant age‐related decline in spatial learning and memory. We then isolated miRNAs from plasma samples collected in all three age groups and the levels of 84 circulating miRNAs were evaluated using a miRNA‐array. The analysis revealed that the levels of miR‐34a, a miRNA previously shown to affect cell survival and promote oxidative stress, were significantly elevated in the 20‐month old group compared to the 4‐month old. Transfection of bEnd.3 cells (BMVECs culture model) with miR‐34a resulted in a reduction in Sirtuin1 (SIRT1) protein levels. In addition, miR‐34a transfected cells showed higher intracellular concentration of reactive oxygen species and increased caspase‐3 cleavage upon treatment with hydrogen peroxide. These results suggest that miR‐34a impairs the ability of brain endothelial microvascular cells to respond to oxidative insult by affecting SIRT1 pathway. Support: UNILIVER and USDA funding 58‐1950‐0‐014