Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

Abstract

Ginsenoside 20(R/S)‐Rg3, as a natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)‐Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)‐Rg3 stereoisomers in the PPARγ ligand‐binding domain (PPARγ‐LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)‐Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPARγ activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)‐Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)‐isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.

Functional roles and mechanisms of ginsenosides from Panax ginseng in atherosclerosis

“…In addition, Rd specially regulates the development of AS via calcium channel. Interestingly, differential binding modes of Rg3 stereoisomers in the PPARc-LBD contribute to differential PPARc activation at the cellular level [ 92 ]. Rg3, which contains 2 neighbouring hydroxyl groups near and on the chiral centre C-20, can act as a natural ligand of PPARc, whereas the PPARc agonist activity of 20(S)-Rg3 is 10 times stronger than that of 20(R)-Rg3 in angiogenesis assay.…”

RING finger protein 10 attenuates vascular restenosis by inhibiting vascular smooth muscle cell hyperproliferation in vivo and vitro

“…Cell proliferation was measured using the Cell Count Kit‐8 (CCK8) assays (Beyotime, China) and the Cell‐Light™ EdU assay (Beyotime, China) according to the manufacturer's directions . VSMCs were cultured at 80–90% confluence and starved with free serum for 24 h. Cells were infected for 48 h with adenoviruses containing the coding sequences of different genes.…”

Advanced Glycation End Products Induce Proliferation and Migration of Human Aortic Smooth Muscle Cells through PI3K/AKT Pathway

“…Yoon et al [26] confirmed that AGEs could initiate their proproliferative function on VSMCs by activating the pathways on which P38 and ERK are dependent. The PI3K/AKT pathway has been found having the function of regulating multiple target proteins to participate in cell proliferation and migration [9,12,27]. Shi et al [28] reported that Irisin stimulates cell proliferation and invasion by targeting the PI3K/AKT pathway in human hepatocellular carcinoma.…”

“…AS is a chronic and complicated process involving numerous types of cells and cell-to-cell interactions that ultimately lead to progression from the “fatty streak” to formation of more complex atherosclerotic plaques [ 11 ]. In the early stage, damage to the vessel intima can initiate a series of self-repair, but excessive proliferation and migration of VSMCs accelerate progression of AS [ 12 ]. Studies found that AGEs largely exist in the arterial lipid stripes, atherosclerotic plaques, and macrophages of DM patients, the quantity of which is positively related to the severity of atherosclerotic plaques [ 13 – 16 ], which means AGEs can accelerate the development of AS in diabetics.…”