B56α subunit of protein phosphatase 2A mediates retinoic acid-induced decreases in phosphorylation of endothelial nitric oxide synthase at serine 1179 and nitric oxide production in bovine aortic endothelial cells

Jung-Hyun Park, Hye Youn Sung, Jee Young Lee, Hyun Jin Kim, Jung-Hyuck Ahn, Inho Jo
Biochemical and Biophysical Research Communications 2013 January 11, 430 (2): 476-81
We previously showed that all-trans retinoic acid (atRA) decreased nitric oxide (NO) production through Akt-mediated decreased phosphorylation of endothelial NO synthase at serine 1179 (eNOS-Ser(1179)) in bovine aortic endothelial cells (BAEC). Since protein phosphatase 2A (PP2A) was also reported to decrease eNOS-Ser(1179) phosphorylation, we investigated using BAEC whether PP2A mediates atRA-induced eNOS-Ser(1179) dephosphorylation and subsequent decreased NO production. Treatment with okadaic acid (5nM), a selective PP2A inhibitor, or ectopic expression of small interference RNA (siRNA) of PP2A catalytic subunit α (PP2A Cα) significantly increased eNOS-Ser(1179) phosphorylation and NO production. Each treatment also significantly reversed atRA-induced observed effects, suggesting a role for PP2A. We also found that atRA significantly increased cellular PP2A activity. However, Western blot analysis revealed that atRA did not increase the expression of PP2A Cα, although it significantly increased the level of B56α of PP2A regulatory B subunit (PP2A B56α), but not PP2A B55α and PP2A B56δ. Real-time PCR assay confirmed a significant increase in PP2A B56α mRNA expression in atRA-treated cells. Ectopic expression of siRNA of PP2A B56α significantly reversed atRA-induced inhibitory effects on eNOS-Ser(1179) phosphorylation and NO production, suggesting a role for PP2A B56α. Our study demonstrates for the first time that atRA decreases eNOS-Ser(1179) phosphorylation and NO release at least in part by increasing PP2A B56α-mediated PP2A activity in BAEC.

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