Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE–/– Mice by Skewing Macrophages to the M2 Phenotype

Abstract

Atherosclerosis (AS) in diabetic patients is often associated with low stability, which might be largely attributed to unfavorable macrophage polarization and increased inflammatory response induced by hyperglycaemia. Ginsenoside Rg3 is one of the main active principles of Panax Ginseng, which has been reported to be a natural ligand of peroxisome proliferator-activated receptor-gamma (PPARγ), a key nuclear transcriptional factor involved in inflammation and macrophage differentiation. However, it remains unclear if Rg3 could exert protective effects on plaque stability in diabetes. In this study, we investigated the role of ginsenoside 20(S)-Rg3 in macrophage polarization and AS plaque stability using advanced glycation end products-treated macrophages and diabetic AS mice models. In vitro, advanced glycation end products (AGEs) treatment promoted the expression of proinflammatory molecules and M1 surface markers, whereas 20(S)-Rg3 could reverse the M1 polarization to the M2 phenotype. In vivo, the administration of 20(S)-Rg3 promoted AS lesion stability and reduced the plaque burden, accompanied by increased M2 macrophages and reduced M1 macrophages. In addition, PPARγ antagonist GW9662 co-administration mostly blocked these effects, suggesting the important role of PPARγ pathways in mediating 20(S)-Rg3 effects in macrophage polarization and atherosclerosis progression. Together, these results demonstrated an immunomodulatory role of ginsenoside 20(S)-Rg3 in promoting macrophages to a profile of the M2 type through PPARγ-dependent mechanisms, and indicated a potential role of 20(S)-Rg3 in the prevention and treatment of diabetic atherosclerosis.

Pro-Resolving Effect of Ginsenosides as an Anti-Inflammatory Mechanism of Panax ginseng

“…In another study, Guo et al showed a similar observation [59]. Treatment of advanced glycation end products promoted the expression of M1 markers (iNOS and CD86) and pro-inflammatory molecules, whereas ginsenoside Rg3 reversed the M1 polarization to the M2 phenotype expressing arginase 1 and CD206 (i.e., mannose receptor), two M2 markers in vitro [59]. The administration of ginsenoside Rg3 promoted atherosclerotic plaque stability, which was accompanied by increased M2 phenotype macrophages and reduced M1 phenotype macrophages in the plaque [59].…”

“…In another study, Guo et al showed a similar observation [59]. Treatment of advanced glycation end products promoted the expression of M1 markers (iNOS and CD86) and pro-inflammatory molecules, whereas ginsenoside Rg3 reversed the M1 polarization to the M2 phenotype expressing arginase 1 and CD206 (i.e., mannose receptor), two M2 markers in vitro [59].…”

“…Treatment of advanced glycation end products promoted the expression of M1 markers (iNOS and CD86) and pro-inflammatory molecules, whereas ginsenoside Rg3 reversed the M1 polarization to the M2 phenotype expressing arginase 1 and CD206 (i.e., mannose receptor), two M2 markers in vitro [59]. The administration of ginsenoside Rg3 promoted atherosclerotic plaque stability, which was accompanied by increased M2 phenotype macrophages and reduced M1 phenotype macrophages in the plaque [59]. By means of a PPARγ antagonist, GW9662, the important role of PPARγ pathways was suggested in mediating ginsenoside Rg3 effects in macrophage polarization and atherosclerotic plaque stability [59].…”

“…The administration of ginsenoside Rg3 promoted atherosclerotic plaque stability, which was accompanied by increased M2 phenotype macrophages and reduced M1 phenotype macrophages in the plaque [59]. By means of a PPARγ antagonist, GW9662, the important role of PPARγ pathways was suggested in mediating ginsenoside Rg3 effects in macrophage polarization and atherosclerotic plaque stability [59].…”

20(S)-Ginsenoside Rg3 Protects Kidney from Diabetic Kidney Disease via Renal Inflammation Depression in Diabetic Rats

“…20(S)-Rg3 is a compound that has many biological effects of preventing ischemia-reperfusion injury, reducing oxygen free radicals, antioxidation, and inhibiting the activity of voltage-regulated pathways. Studies have reported that 20(S)-Rg3 as a nontraditional therapy has protective effects on diabetes itself, as well as diabetic cardiomyopathy, diabetic retinopathy, and atherosclerosis in DM [23,24]. Kang et al [20] reported 20(S)-Rg3 prevents the progression of renal damage and dysfunction in type 2 diabetic rats via inhibiting oxidative stress and advanced glycation end-product formation.…”