miR‐181b regulates vascular endothelial aging by modulating an MAP3K3 signaling pathway
Haoyang Zhou, Dafeng Yang, Henry S. Cheng, Michael McCoy, Daniel Pérez‐Cremades, Stefan Haemmig, Danny Wong, Lei Chen, Mark W. Feinberg
Abstract
Abstract Endothelial cell (EC) aging plays a vital role in the pathogenesis of cardiovascular disease (CVD). MicroRNAs have emerged as crucial regulators of target gene expression by inhibiting mRNA translation and/or promoting mRNA degradation. We identify an aging‐related and oxidative stress‐responsive microRNA, miR‐181b, that inhibits endothelial cell apoptosis and senescence. In gain‐ or loss‐of‐function studies, miR‐181b regulated the expression of key apoptosis markers (Bcl2, Bax, cleaved‐Caspase3) and senescence markers (p16, p21, γH2AX) and the ratio of apoptotic cells (TUNEL‐positive) and senescent cells (SA‐βgal‐positive) in H 2 O 2 ‐induced ECs. Mechanistically, miR‐181b targets MAP3K3 and modulates a MAP3K3/MKK/MAPK signaling pathway. MAP3K3 knockdown recapitulated the phenotype of miR‐181b overexpression and miR‐181b was dependent on MAP3K3 for regulating EC apoptosis and senescence. In vivo, miR‐181b expression showed a negative correlation with increasing age in the mouse aorta. Endothelial‐specific deficiency of miR‐181a2b2 increased the target MAP3K3, markers of vascular senescence (p16, p21), and DNA double‐strand breaks (γH2AX) in the aorta of aged mice. Collectively, this study unveils an important role of miR‐181b in regulating vascular endothelial aging via an MAP3K3‐MAPK signaling pathway, providing new potential therapeutic targets for antiaging therapy in CVD.