Artemisinin Attenuated Atherosclerosis in High-Fat Diet–Fed ApoE−/− Mice by Promoting Macrophage Autophagy Through the AMPK/mTOR/ULK1 Pathway

Abstract

Artemisinin is an endoperoxide sesquiterpene lactone from Artemisia annua L with multiple beneficial effects, including anti-inflammation, antioxidant, and vascular protection. Recent studies have found that inflammation along with autophagy deficiency in macrophages is the possible reason for foam cell accumulation in the intima, which leads to atherosclerotic plaque formation. The primary aims of this study were to explore the inhibiting effect of artemisinin on atherosclerosis in high-fat diet–fed ApoE−/− mice and investigate the probable mechanism. Artemisinin (50 and 100 mg/kg, intragastric administration) treatment effectively inhibited foamy macrophage transformation and decreased atherosclerotic plaque formation in atherosclerotic mice. Moreover, artemisinin promoted AMP-activated protein kinase (AMPK) activation, inhibited mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinase 1 (ULK1) phosphorylation, and increased LC-3II accumulation and P62 degradation, thereby enhancing macrophage autophagy. Besides, the inhibiting effect of artemisinin on mTOR and ULK1 phosphorylation could be abrogated by AMPK knockdown, suggesting AMPK was the essential target of artemisinin on promoting macrophage autophagy. Our study indicated that artemisinin alleviated atherosclerotic lesions by accelerating macrophage autophagy through the AMPK/mTOR/ULK1 pathway.

The Potential Roles of Artemisinin and Its Derivatives in the Treatment of Type 2 Diabetes Mellitus

“…On the other hand, a deficiency of macrophage autophagy accelerates foamy macrophage transformation (Shao et al, 2016). Treating HFD-fed ApoE-/-mice with 50, 100 mg/kg/d artemisinin for 8 weeks successfully attenuated foamy macrophage transformation and enhanced macrophage autophagy (Cao et al, 2020). Similar results were obtained in the experiments performed in vitro.…”

“…Abundant evidence shows that after artemisinin therapy, the area of aortic root lesions shrunk, vascular smooth muscle cell hyperplasia and fibrosis were attenuated, and the progression of atherosclerosis lesion formation was diminished, indicating the potential therapeutic effects on atherosclerosis, which is one of the most common manifestations of diabetic cardiovascular disease. Thus, we deduced that artemisinins may alleviate diabetic cardiovascular disease by inhibiting the occurrence and development of atherosclerosis (Wang et al, 2013;Jiang et al, 2016;Du et al, 2019;Cao et al, 2020;Jiang et al, 2020).…”

“…Similar results were obtained in the experiments performed in vitro. Mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinase 1 (ULK1) phosphorylation was inhibited upon artemisinin administration, and some autophagic markers were increased, such as LC-3II, which accumulated, and P62 was degraded, showing the enhancement of macrophage autophagy in the oxLDL-treated mouse macrophage cell line (Cao et al, 2020). Furthermore, inflammation disturbs the normal function of vascular endothelial cells and smooth muscle cells (Reglero-Real et al, 2016;Li et al, 2018).…”

The potential role of sesquiterpene lactones isolated from medicinal plants in the treatment of the metabolic syndrome – A review

“… COX-2 inhibition. Cavin et al., 2005 18 Artemisinin Cadinanolide Artemisia annua Vascular protection ( in vivo ) Antidiabetic ( in vivo ) MCP-1, IFN-γ, IL-6 and TNF-α (↓) Inhibition of atherosclerotic plaque formation Promote the conversion of pancreatic glucagon-producing α cells to insulin-secreting β cells Cao et al., 2020 ; Li et al., 2017 19 Scoporanolide Guaianolide Artemisia scoparia Antihypertensive ( in vivo ) Inhibition of plasma ACE activity Cho et al., 2016 20 Estafiatin 21 Cumambrin A Guaianolide Chrysanthemum boreale Antihypertensive ( in vivo ) Vasorelaxant ( ex vivo ) Normalization of blood pressure Hong et al., 1999 , 2005 Reduction (↓); increment (↑); thiobarbituric acid reactive substances (TBARS); reduced glutathione (GSH); superoxide dismutase (SOD); catalase (CAT); glutathione peroxidase (GPx); insulin resistance (IR); Toll-like receptor 4 (TLR4); c-Jun N-terminal kinases (JNK); interleukin 6 (IL-6); monocyte chemoattractant protein 1 (MCP-1); Apolipoprotein C3 (APOC3); AMP-activated protein kinase (AMPK); peroxisome proliferator-activated receptors α and γ (PPARα/γ); nuclear factor kappa B (NF-κB); transforming growth factor beta (TGF-β1); fibronectin (FN); glucose-6-phosphatase (G6Pase); glucokinase (GK); cyclooxygenase 2 (COX-2); interferon-gamma (IFN-γ); tumor necrosis factor α (TNF-α); angiotensin I-converting enzyme (ACE). …”

“…Experimental studies have also established their effectiveness as an anti-inflammatory, antioxidant, anti-tumor, and vascular protection agent ( Kim et al., 2015 ; Jiang et al., 2016 ; Efferth, 2017 ). Regarding to vascular protection, Cao et al. (2020 ) demonstrated that oral administration of artemisinin ( 18 ) effectively alleviated inflammatory response (MCP-1, IFN-γ, IL-6 and TNF-α), elevated macrophage autophagy, suppressed foamy macrophage transformation, and thereby inhibiting atherosclerotic plaque formation in high-fat diet treated ApoE −/− mice.…”