Geniposide Enhances Macrophage Autophagy through Downregulation of TREM2 in Atherosclerosis

Abstract

Macrophage autophagy defect is closely related to the progression of atherosclerosis (AS) and is regulated by the triggering receptor expressed on myeloid cell 2 (TREM2). TREM2 is a key factor in the development of Alzheimer’s disease (AD), the deficiency of which leads to anomalous autophagy in microglia. However, the role of TREM2 in the autophagy of plaque macrophages is still unclear. Geniposide (GP) can inhibit AS progression and enhance macrophage autophagy, although the underlying mechanisms remain unknown. We found that high-fat diet (HFD) feeding significantly increased TREM2 levels and inhibited autophagy in the macrophages of ApoE[Formula: see text] mice. TREM2 overexpression in RAW264.7 macrophages decreased autophagy via activation of mTOR signaling. GP inhibited the progression of AS in ApoE[Formula: see text] mice, reinforced macrophage autophagy, and downregulated TREM2 by inhibiting mTOR signaling. Taken together, augmenting the autophagy levels in plaque macrophages by inhibiting the TREM2/mTOR axis can potentially impede atherosclerotic progression. The promising therapeutic effects of GP seen in this study should be validated in future trials, and the underlying mechanisms have to be elucidated in greater detail.

Geniposide Combined With Notoginsenoside R1 Attenuates Inflammation and Apoptosis in Atherosclerosis via the AMPK/mTOR/Nrf2 Signaling Pathway

“…GP and NR1 are active compounds extracted from G. jasminoides Ellis and notoginseng, respectively. It has been proven that GP or NR used alone can alleviate the occurrence and development of AS ( Jia et al, 2014 ; Xu et al, 2020 ). GN combination is a patented and approved TCM drug for the prevention and treatment of AS, whose effect is better than that of GP or NR used alone.…”

“…ApoE −/− mice were fed an HFD for 12 weeks to establish the AS model, while the Con group mice were fed a normal diet. After 12 weeks, the GP, NR, and GN groups were respectively given geniposide (50 mg kg −1 ), Panax notoginseng R1 (50 mg kg −1 ) and geniposide + notoginsenoside R1 (50 + 50 mg kg −1 ) by intraperitoneal injection for 12 weeks ( Xiao et al, 2018 ; Xu et al, 2020 ), and the remaining control mice were treated with the same volume of normal saline. After the last administration, the body weight and fasting blood glucose of all mice were detected.…”

“…Geniposide (GP) is an iridoid glycoside extracted from the dried fruits of Gardenia jasminoides Ellis, which is its main active substance. Recent studies have found that GP could inhibit the occurrence and development of AS by inhibiting inflammation, alleviating lipid metabolism disorder, regulating macrophage polarization and enhancing autophagy ( Cheng et al, 2019 ; Jin et al, 2020 ; Liu et al, 2020 ; Xu et al, 2020 ). Notoginsenoside R1 (NR) is a characteristic component of traditional Chinese medicine Panax notoginseng, which have been clinically used to treat cardiovascular and cerebral vascular diseases in China due to its good effect in controlling internal and external bleeding, improving blood stasis and reducing blood pressure ( Wang et al, 2016 ; Yang et al, 2020 ).…”

Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

“…Decreases the size of atherosclerotic plaques (Xu Y. L. et al, 2020) formation characterized by LC3 production and p62 degradation and suppress palmitic acid-induced ROS to attenuate endothelial oxidative injury in HUVECs (Zhou et al, 2019).…”

“…Previous study demonstrated that geniposide decreased the size of atherosclerotic plaques, inhibited the progression of atherosclerosis in high fat diet-fed ApoE −/− mice. The potential mechanism may contribute to the reinforce of macrophage autophagy by inhibiting the triggering receptor expressed on myeloid cell 2 (TREM2)/mTOR signaling (Xu Y. L. et al, 2020).…”