Formononetin induces vasorelaxation in rat thoracic aorta via regulation of the PI3K/PTEN/Akt signaling pathway

Abstract

BackgroundFormononetin (FMN) is an isoflavone that produces arterial vasodilation. However, the underlying molecular mechanisms are unclear.PurposeThe purpose of this study was to explore the vasorelaxant effect and the potential mechanism of FMN in vascular endothelium in isolated rat aorta.MethodsThe thoracic aortas of Sprague Dawley rats were isolated to test the arterial reactivity in the presence of FMN with or without inhibitors. Bioinformatics analyses, including a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and molecular docking methods, were performed to predict therapeutic targets responsible for the vascular protection produced by FMN. We used rat aortic endothelial cells (RAOECs) as an in vitro model to verify the potential mechanism through molecular biological analyses. The production of nitric oxide (NO) metabolites were evaluated via an NO assay kit according to the manufacturer’s instruction. The mRNA expression of eNOS was analyzed by polymerase chain reaction, and the protein levels of PTEN, phosphorylated Akt, and eNOS were measured by Western blot.ResultsWe found that FMN dilated rat aortic rings in a concentration-dependent manner, which was reduced by endothelium denudation and eNOS inhibition. The bioinformatics analyses indicated that FMN activity was associated with the PI3K/PTEN/Akt signaling pathway. Molecular biological studies demonstrated that FMN significantly elevated the levels of NO and eNOS mRNA and markedly increased the protein expression of phosphorylated Akt and eNOS in RAOECs, and decreased PTEN compared with a dimethyl sulfoxide group.ConclusionFMN performs vasorelaxation of the thoracic aorta through activating the PI3K/PTEN/Akt signaling pathway.

The Vascular Effects of Isolated Isoflavones—A Focus on the Determinants of Blood Pressure Regulation

“…Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a regulatory enzyme that dephosphorylates PIP 3 , leading to Akt suppression. Formononetin binds PTEN, preventing the suppression of the PI3K/PTEN/Atk pathway, therefore contributing to vasorelaxation [ 169 ]. In the rat mesenteric arteries, formononetin-mediated relaxation is partly attributed to the upregulation of eNOS, since it is attenuated by ICI 182,780 [ 170 ].…”

Biochanin A, the Most Potent of 16 Isoflavones, Induces Relaxation of the Coronary Artery Through the Calcium Channel and cGMP-dependent Pathway

“…Interestingly, isoformononetin, tectorigenin, and cladrin appeared more potent than daidzein in this study. Previous articles showed different potencies of several isoflavones on various arteries [5,7,11,15,16,[19][20][21][22]. Small discrepancies between the aforementioned studies might derive from the use of different animal, breed, or tissue models or may be due to different vasoconstrictors used to precontract the tested arteries.…”

“…), Prunus, Pueraria, and Ononis sp. [5][6][7][8]. Isoflavonoid intake in humans is also increasing due to the use of a variety of dairy products, processed food, and food supplements derived from the aforementioned plants [9,10].…”

Formononetin ameliorates muscle atrophy by regulating myostatin‐mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease

“…Formononetin (FMN) is a bioactive isoflavone compound appeared in Chinese medicinal ingredients, such as Astragalus membranaceus . Recent research has found that FMN has multiple pharmacological effects, including anti‐inflammatory, antioxidant, antitumor and vasorelaxant benefits 26‐28 . Several studies have demonstrated the anti‐inflammatory action of FMN.…”

“…Recent research has found that FMN has multiple pharmacological effects, including anti-inflammatory, antioxidant, antitumor and vasorelaxant benefits. [26][27][28] Several studies have demonstrated the anti-inflammatory action of FMN. One showed that FMN down-regulated TNF-α, IL-6 and IL-1β in a lipopolysaccharide (LPS)-induced zebrafish with lipidomics and targeted transcriptomics.…”