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Fisetin Inhibits Akt Phosphorylation in Human Endothelial Cells

In a screening of polyphenolic compounds, fisetin reduced Ser473 phosphorylation of Akt by 28% in human endothelial cells. This reaction was surprisingly rapid and was observed after only 5 minutes of treatment with 10 µM. Excessive activation of Akt signaling has been associated with diabetic complications such as abnormal angiogenesis. Therefore, moderate suppression of Akt activity may have a protective effect. In addition, this study also reveals structural features that allow flavonoids to act more effectively as Akt inhibitors.

Meta

Date: 06-2019

Evidence type: Journal Article, Research Support, Non-U.S. Gov't

Compounds: Fisetin

Effects: akt phosphorylation inhibition

PMID 31195734

LongevityDB interpretation

The research team screened 44 types of polyphenolic compounds, belonging to nine structural subclasses, for their inhibitory effect on Akt phosphorylation in human endothelial cells. Immortalised cell line Ea.hy926 and primary HUVEC were used in the experiment and treated with 10 µM for 5 minutes assuming acute exposure.

In primary screening using ELISA, fisetin, a flavonol, reduced phosphorylation in Ser473 by 28% (±9%, n=3). This inhibitory effect was also confirmed by Western blotting and a strong correlation was observed between two phosphorylation sites, Ser473 and Thr308. The compounds showing the most potent inhibitory effect were luteolin (44%), quercetin (36%), urolithin A (35%), apigenin (32%) and fisetin (28%).

Structure-activity relationship analysis revealed that the C2=C3 double bond in the A-ring, the hydroxyl groups at the C5 and C7 positions and the catecholic hydroxyl pattern in the B-ring are advantageous structural elements contributing to inhibitory activity, whereas glycosylation, such as glucosyl, completely eliminates the activity. These results indicate that some flavonoids can suppress Akt hyperactivation, and their clinical effects are interesting because excessive Akt activity is associated with diabetic microvascular complications and pathological angiogenesis.

  • Model: human endothelial cells (Ea.hy926, HUVEC)
  • Intervention: 44 polyphenols, 10 µM, 5 min treatment
  • Primary endpoint: Akt phosphorylation in Ser473 (ELISA) and Thr308 (Western blot)
  • Fisetin results: 28% inhibition of pAkt Ser473
  • Limitations: Results are only for acute exposure conditions in vitro, long-term effects and in vivo effects are unknown.