Study summary · research use only
FoxO4 controls sGCβ transcription in vascular smooth muscle
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study using rat aortic smooth muscle cells (SMCs) and human aortic SMCs, researchers investigated the role of FoxO transcription factors in regulating soluble guanylyl cyclase β (sGCβ) expression. Using FoxO shRNA knockdown adenovirus in rat aortic SMCs, FoxO1 or FoxO3 knockdown produced greater than twofold increases in Gucy1a3 and Gucy1b3 mRNA, without changes in NO-dependent cGMP production. FoxO4 knockdown produced a 50% decrease in Gucy1a3 and Gucy1b3 mRNA, with 70% loss of sGCα and 50% loss of sGCβ protein, and decreased cGMP production and downstream phosphorylation by more than 50%. Triple FoxO knockdown further reduced sGC-dependent function. Using promoter luciferase and chromatin immunoprecipitation assays in human aortic SMCs, the authors report FoxO4 directly binds FoxO DNA motifs in the GUCY1B3 promoter region.
Abstract
Nitric oxide (NO) binds soluble guanylyl cyclase β (sGCβ) to produce cGMP and relax vascular smooth muscle cells (SMCs) needed for vasodilation. Although the regulation of NO-stimulated sGC activity has been well characterized at the posttranslational level, the mechanisms that govern sGC transcription remain incompletely understood. Recently, we identified Forkhead box subclass O (FoxO) transcription factors as essential for expression of sGC; however, the specific FoxO family member responsible for the expression of sGCβ in SMC remains unknown. Using FoxO shRNA knockdown adenovirus treatment in rat aortic SMCs, we show that FoxO1 or FoxO3 knockdown causes greater than twofold increases in Gucy1a3 and Gucy1b3 mRNA expression, without changes in NO-dependent cGMP production or cGMP-dependent phosphorylation. FoxO4 knockdown produced a 50% decrease in Gucy1a3 and Gucy1b3 mRNA with 70% loss of sGCα and 50% loss of sGCβ protein expression. Knockdown of FoxO4 expression decreased cGMP production and downstream protein kinase G-dependent phosphorylation more than 50%. Triple FoxO knockdown exacerbated loss of sGC-dependent function, phenocopying previous FoxO inhibition studies. Using promoter luciferase and chromatin immunoprecipitation assays, we find that FoxO4 acts as a transcriptional activator by directly binding several FoxO DNA motifs in the promoter regions of GUCY1B3 in human aortic SMCs. Collectively, our data show FoxO4 is a critical transcriptional regulator of sGCβ expression in SMC.NEW & NOTEWORTHY One of the key mechanisms of vascular smooth muscle cell (SMC) dilation occurs through nitric oxide (NO)-dependent induction of soluble guanylyl cyclase (sGC) by means of its β-subunit. Herein, we are the first to identify Forkhead box subclass O protein 4 (FoxO4) as a key transcriptional regulator of GUCY1B3 expression, which codes for sGCβ protein in human and animal SMCs. This discovery will likely have important implications for the future usage of antihypertensive and vasodilatory therapies which target NO production, sGC, or FoxO transcription factors.
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