A PPAR gamma-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis

作者：Lee Aram; Papangeli Irinna; Park Youngsook; Jeong Ha Neul; Choi Jihea; Kang Hyesoo; Jo Ha Neul; Kim Jongmin; Chun Hyung J

来源：Scientific Reports, 2017, 7(1): 2528.

DOI：10.1038/s41598-017-02852-4

Activation of the endothelium by pro-inflammatory stimuli plays a key role in the pathogenesis of a multitude of vascular diseases. Angiogenesis is a crucial component of the vascular response associated with inflammatory signaling. The CD40/CD40 ligand dyad in endothelial cells (EC) has a central role in promoting vascular inflammatory response; however, the molecular mechanism underlying this component of inflammation and angiogenesis is not fully understood. Here we report a novel microRNA mediated suppression of endothelial CD40 expression. We found that CD40 is closely regulated by miR-424 and miR-503, which directly target its 3' untranslated region. Pro-inflammatory stimuli led to increased endothelial CD40 expression, at least in part due to decreased miR-424 and miR-503 expression. In addition, miR-424 and miR-503 reduced LPS induced EC sprouting, migration and tube formation. Moreover, we found that miR-424 and miR-503 expression is directly regulated by peroxisome proliferator-activated receptor gamma (PPAR gamma), whose endothelial expression and activity are decreased in response to inflammatory factors. Finally, we demonstrate that mice with endothelial-specific deletion of miR-322 (miR-424 ortholog) and miR-503 have augmented angiogenic response to LPS in a Matrigel plug assay. Overall, these studies identify a PPAR gamma-dependent miR-424/503-CD40 signaling axis that is critical for regulation of inflammation mediated angiogenesis.

• 出版日期2017-5-31