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

Abstract

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 IC50 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.

Protoilludane-Type and Related Nor-Sesquiterpenes from Phellinus hartigii and Their Anti-Hypertrophic Activities in Rat Cardiomyocytes

“…Pathologic cardiac hypertrophy, an autonomous risk determinant, accentuates the likelihood of escalated morbidity and mortality within heart failure. 18 Effectively addressing pathologic cardiac hypertrophy assumes paramount significance in decelerating the progression from cardiac insufficiency to heart failure. Despite the endeavors of researchers in this realm in recent times, a satisfactory clinical remedy for this pathological transformation remains elusive.…”

Parkia speciosa Hassk. Empty Pod Extract Prevents Cardiomyocyte Hypertrophy by Inhibiting MAPK and Calcineurin-NFATC3 Signaling Pathways

“…The beneficial effects of the fraction were comparable to those of valsartan, a drug that has been used clinically to reduce cardiac remodeling and its progression to heart failure [ 42 ]. Numerous studies have demonstrated the antihypertrophic properties of some of the compounds that might be present in the fraction, such as gallic acid [ 43 ], quercetin [ 14 ], epigallocatechin-3-gallate [ 44 ], kaempferol [ 45 ], luteolin [ 46 ], and herbacetin [ 47 ].…”

The “Top 50 High Impact Researches of Traditional Medicine” published in 2021

“…This finding holds true in effectively alleviating myocardial hypertrophy, thereby offering potential therapeutic benefits for patients afflicted with heart failure. Moreover, this study provides a new research strategy for efficient discovery of potent compounds from herbal medicines [38] .…”