miR ‐92a aggravates metabolic syndrome via KLF2 / miR ‐483 axis

OBJECTIVE: To exam the role of miR-92a/KLF2/miR-483 in the pathogenesis of metabolic syndrome. METHODS: In this study, the serum of healthy controls and patients with metabolic syndrome were collected to detect the circulating level of miR-92a and miR-483. In vitro cultured HUVECs, overexpression or suppression of miR-92a, miR-483 or KLF2 to determine the relationship among miR-92a, KLF2 and miR-483. Ang II, ox-LDL, or high glucose treatment were used to mimic the metabolic syndrome. HUVECs or HepG2 cells were treated with Telmisartan, Atorvastatin, or metformin, the miR-483 and its target gene expression was detected. In animal experiment, ob/ob mice were chose to confirm the changes of miR-92a, KLF2, and miR-483. RESULTS: Compared with the healthy controls, the level of miR-92a was significantly increased, while miR-483 level was remarkably decreased in the patients with metabolic syndrome. In vitro cultured HUVECS, overexpression of miR-92a significantly reduced the expression of miR-483, but overexpression of miR-483 had no effect on miR-92a. Overexpression of KLF2 could downregulate miR-483 level, while inhibition of KLF2 had the opposite effect. When HUVECs and HepG2 were stimulated with Ang II, ox-LDL and high glucose, the expression of miR-483 was significantly decreased and its target genes was increased. Anti-miR-92a could reverse the effect. Furthermore, Telmisartan, Atorvastatin, and Metformin significantly increased miR-483 expression and decreased its target gene expression, which could be reversed by miR-92a mimic. The level of miR-92a was significantly increased in HepG2 cells, which were treated with exosomes derived from endothelial cells with miR-92a overexpression. ob/ob mice showed the similar effects. CONCLUSIONS: Endothelial dysfunction and fatty liver are critically involved in the pathogenesis of metabolic syndrome. MicroRNAs can mediate the cellular communication between vascular endothelial cells (ECs) and distal cell. Serum miR-92a level was higher in metabolic syndrome patients than controls. KLF2 is the target gene of miR-92a, which can increase the production of miR-483, miR-483 acts on its target genes CTGF, ET-1, and β-catenin to protect cell function. EC miR-92a is secreted out of cells into the blood, circulates through the blood to the liver, and continues to exert its biological effects after being absorbed by hepatocytes. LNA-miR-92a administration reversed endothelial cell damage and fatty liver caused by metabolic syndrome by affecting the KLF2/miR-483 pathway.