Ganoderma triterpenes Protect Against Hyperhomocysteinemia Induced Endothelial-Mesenchymal Transition via TGF-β Signaling Inhibition

Abstract

Endothelial dysfunction is one of the most important pathological status in hyperhomocysteinemia (HHcy) related cardiovascular diseases. Whereas, the underlying mechanisms have not been fully elucidated yet, concomitant with the absence of effective treatment. The purpose of this study was to explore the main mechanisms involved in HHcy-induced endothelial injury and identify the protective effect of Ganoderma triterpenes (GT). Bovine aortic endothelial cells (BAECs) were applied as in vitro experimental model. The small molecular inhibitors were used to explore the signalings involved in HHcy-induced endothelial injury. The experimental results provided initial evidence that HHcy led to endothelial-mesenchymal transition (EndMT). Meanwhile, TGF-β/Smad, PI3K/AKT and MAPK pathways were activated in this process, which was demonstrated by pretreatment with TGF-β RI kinase inhibitor VI SB431542, PI3K inhibitor LY294002, p38 inhibitor SB203580, and ERK inhibitor PD98059. Furthermore, it was found that GT restrained the process of HHcy-induced EndMT via reducing oxidative stress and suppressing fore mentioned pathways with further inhibiting the activity of Snail. These results implicate that there is an untapped potential for GT as a novel therapeutic candidate for HHcy-induced EndMT through alleviating oxidative stress and canonical TGF-β/Smad and non-Smad dependent signaling pathways.

Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways

“…4 ). According to our previous research experience, the terpenes isolated from Ganoderma exert their pharmacological activities often at doses between 6.25 and 100 μg/mL in vitro [ 14 , 15 , 35 , 36 ]. Therefore, we chose 6.25, 25, and 100 μg/mL GA for the in vitro study.…”

“…We recently studied the therapeutic effect of Ganoderma triterpenoids (GTs) on autosomal dominant polycystic kidney disease (ADPKD) [ 15 ] and hyperhomocysteinemia (HHcy)-induced endothelial injury [ 14 ]. GTs exerts a fascinating inhibitory effect on renal cyst development in an ADPKD mouse model via downregulating Ras/mitogen-activated protein kinase (MAPK) signaling and promoting cell differentiation [ 15 ].…”

“…GTs exerts a fascinating inhibitory effect on renal cyst development in an ADPKD mouse model via downregulating Ras/mitogen-activated protein kinase (MAPK) signaling and promoting cell differentiation [ 15 ]. It was determined that, in a bovine aortic endothelial cell model, GT protects against HHcy-induced EMT via inhibiting canonical TGF-β/Smad- and non-Smad-dependent signaling pathways [ 14 ]. Considering the common pathogenesis and signaling pathways, these data strongly suggest that GTs and their components can be developed as novel agents for preventing and treating CKD.…”

Histone modification of endothelial-mesenchymal transition in cardiovascular diseases

“…In addition, TGF-β can also affect the EndMT process by regulating non-Smad pathways, such as ERK/MAPK, PI3K/Akt ( 12 ) and Rho GTPase ( 13 ). Other regulation of EndMT signaling pathways, such as Wnt/β-catenin, Notch and Hippo pathways can participate in EndMT process alone or in conjunction with TGF-β ( 14 – 16 ).…”

Identification of a Novel Metabolic Target for Bioactive Triterpenoids Biosynthesis in Ganoderma lucidum

“…Karst is a precious and famous large fungus as a food and medicine homologous. It is rich in active polysaccharides ( Hu et al, 2019 ), triterpenoids ( He et al, 2019 ), nucleosides ( Chen Y. et al, 2012 ), sterols ( Xu et al, 2021 ), and other substances with extremely high nutritional and medicinal values ( Li et al, 2019a ; Zhao et al, 2019 ). Ganoderma triterpenoids are the main active ingredients of G. lucidum .…”