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Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy

Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and...

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Autores principales: Zhang, Shujing, Wang, Yingchao, Yu, Min, Shang, Ye, Chang, Yanxu, Zhao, Hong, Kang, Yu, Zhao, Lu, Xu, Lei, Zhao, Xiaoping, Difrancesco, Dario, Baruscotti, Mirko, Wang, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805583/
https://www.ncbi.nlm.nih.gov/pubmed/34761560
http://dx.doi.org/10.1002/advs.202101485
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author Zhang, Shujing
Wang, Yingchao
Yu, Min
Shang, Ye
Chang, Yanxu
Zhao, Hong
Kang, Yu
Zhao, Lu
Xu, Lei
Zhao, Xiaoping
Difrancesco, Dario
Baruscotti, Mirko
Wang, Yi
author_facet Zhang, Shujing
Wang, Yingchao
Yu, Min
Shang, Ye
Chang, Yanxu
Zhao, Hong
Kang, Yu
Zhao, Lu
Xu, Lei
Zhao, Xiaoping
Difrancesco, Dario
Baruscotti, Mirko
Wang, Yi
author_sort Zhang, Shujing
collection PubMed
description Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and in vivo. Serum/glucocorticoid regulated kinase 1 (SGK1) is identified as a potential target of Ext. R. By mass spectrometry‐based kinase inhibitory assay, herbacetin (HBT) from Ext.R is identified as a novel SGK1 inhibitor with IC(50) of 752 nmol. Thermal shift assay, KINOMEscan in vitro assay combined with molecular docking proves a direct binding between HBT and SGK1. Site‐specific mutation of Asp177 in SGK1 completely ablates the inhibitory activity of HBT. The presence of —OH groups at the C‐3, C‐8, C‐4’ positions of flavonoids is suggested to be favorable for the inhibition of SGK1 activity. Finally, HBT significantly suppresses cardiomyocyte hypertrophy in vitro and in vivo, reduces reactive oxygen species (ROS) synthesis and calcium accumulation. HBT decreases phosphorylation of SGK1 and regulates its downstream forkhead box protein O1 (FoxO1) signaling pathway. Taken together, the findings suggest that a panel of flavonoids structurally related to HBT may be novel leads for developing new therapeutics against cardiac hypertrophy.
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spelling pubmed-88055832022-02-04 Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy Zhang, Shujing Wang, Yingchao Yu, Min Shang, Ye Chang, Yanxu Zhao, Hong Kang, Yu Zhao, Lu Xu, Lei Zhao, Xiaoping Difrancesco, Dario Baruscotti, Mirko Wang, Yi Adv Sci (Weinh) Research Articles Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and in vivo. Serum/glucocorticoid regulated kinase 1 (SGK1) is identified as a potential target of Ext. R. By mass spectrometry‐based kinase inhibitory assay, herbacetin (HBT) from Ext.R is identified as a novel SGK1 inhibitor with IC(50) of 752 nmol. Thermal shift assay, KINOMEscan in vitro assay combined with molecular docking proves a direct binding between HBT and SGK1. Site‐specific mutation of Asp177 in SGK1 completely ablates the inhibitory activity of HBT. The presence of —OH groups at the C‐3, C‐8, C‐4’ positions of flavonoids is suggested to be favorable for the inhibition of SGK1 activity. Finally, HBT significantly suppresses cardiomyocyte hypertrophy in vitro and in vivo, reduces reactive oxygen species (ROS) synthesis and calcium accumulation. HBT decreases phosphorylation of SGK1 and regulates its downstream forkhead box protein O1 (FoxO1) signaling pathway. Taken together, the findings suggest that a panel of flavonoids structurally related to HBT may be novel leads for developing new therapeutics against cardiac hypertrophy. John Wiley and Sons Inc. 2021-11-10 /pmc/articles/PMC8805583/ /pubmed/34761560 http://dx.doi.org/10.1002/advs.202101485 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhang, Shujing
Wang, Yingchao
Yu, Min
Shang, Ye
Chang, Yanxu
Zhao, Hong
Kang, Yu
Zhao, Lu
Xu, Lei
Zhao, Xiaoping
Difrancesco, Dario
Baruscotti, Mirko
Wang, Yi
Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title_full Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title_fullStr Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title_full_unstemmed Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title_short Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy
title_sort discovery of herbacetin as a novel sgk1 inhibitor to alleviate myocardial hypertrophy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805583/
https://www.ncbi.nlm.nih.gov/pubmed/34761560
http://dx.doi.org/10.1002/advs.202101485
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