Endothelial dysfunction plays an essential role in the pathogenesis of diabetic vascular diseases. Our previous studies showed exercise improves endothelial function in diabetic mice partially through AMPK pathway. MicroRNA 181b (miR-181b) was reported to inhibit NF-κB activity in endothelial cells. However, it is still unknown whether miR-181b is regulated by AMPK signaling and involved in the vasoprotective effect of exercise. The present study investigated the expression of miR-181b in aortas from diabetic mice with/without exercise and reveals a role of the AMPK in exercise-induced miR-181b expression. We first determined the miR-181b level in the aortas of diabetic db/db mice subjected to treadmill exercise (45 min/day for eight weeks). The results showed that exercise significantly increased miR-181b level in the endothelium of mouse aorta compared to the sedentary mice. To test whether the increased blood flow during exercise affects miR-181b expression, we tested the effect of laminar flow on miR-181b expression in Human Umbilical Vein Endothelial Cells (HUVECs). Laminar flow greatly increases miR-181b expression. To understand the mechanism for flow-induced miR-181b expression, we treated HUVECs with AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and found that AICAR-induced miR-181b expression is reversed by AMPK inhibitors. Furthermore, we infected db/db mice with the adenovirus over-expressing miR-181b. MiR-181b overexpression improved endothelial function in db/db mice accompanied by decreased vascular inflammation and increased eNOS expression in mouse arteries. In summary, exercise increases miR-181b level in mouse endothelium probably via shear stress-induced AMPK activation. MiR-181b improves endothelial function in diabetic mice by inhibiting vascular inflammation and increasing eNOS expression. The present results suggest the therapeutic potential of targeting miR-181b against diabetic vasculopathy.
W. Shang: None. Y. Wang: None. J. Luo: None. X. Tian: None. L. Wang: None. Y. Huang: None.
Hong Kong Research Grants Council/Collaborative Research Fund (C4024-16W); Hong Kong Health and Medical Research Fund (05161746)