Leonurine Prevents Atherosclerosis Via Promoting the Expression of ABCA1 and ABCG1 in a Pparγ/Lxrα Signaling Pathway-Dependent Manner

Abstract

Background/Aims: Previous studies have demonstrated that leonurine, a unique alkaloid compound of Herba leonuri, can exert anti-oxidative and anti-inflammatory effects on the development of atherosclerosis (AS). This study was designed to investigate the effects of leonurine on cholesterol efflux from THP-1 macrophage-derived foam cells and development of atherosclerotic lesions in apoE^-/- mice, and further determine the potential mechanisms. Methods: Human THP-1 cells were fully differentiated into foam cells by the pre-treatment with phorbol-12-myristate-13-acetate (PMA) and oxidized density lipoproteins (ox-LDL). After cells were incubated with various concentrations of leonurine, Oil Red O staining and high-performance liquid chromatography (HPLC) assays were utilized to detect cellular lipid accumulation and cholesterol content, respectively. Cellular cholesterol efflux was determined by liquid scintillation counting. The mRNA and protein levels of ATP-binding cassette transporter A1/G1 (ABCA1/G1), peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) in foam cells were assessed using real-time quantitative PCR (RT-qPCR) and western blot analyses, respectively. Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) levels in apoE^-/- mice were evaluated using enzymatic methods. The atherosclerotic lesion sizes and collagen contents in aortic roots were determined by Oil Red O and Masson’s trichrome staining, respectively. Results: Oil Red O staining and liquid scintillation counting assays showed that leonurine significantly inhibited lipid accumulation and promoted ³H-cholesterol efflux in human THP-1 macrophage-derived foam cells in a concentration-dependent manner. Besides, both the mRNA and protein levels of ABCA1/G1, PPARγ and LXRα were enhanced by leonurine, which were attenuated by LXRα siRNA or PPARγ siRNA transfection. Finally, leonurine improved plasma lipid profile, decreased atherosclerotic lesion sizes, increased collagen contents and amplified PPARγ, LXRα and ABCA1/G1 expressions in aortic roots of apoE^-/- mice. Conclusions: Leonurine can promote cholesterol efflux and alleviate cellular lipid accumulation by magnifying the expression of ABCA1/G1 in a PPARγ/LXRα signaling pathway-dependent manner in human THP-1 macrophage-derived foam cells and abate atherogenesis in apoE^-/- mice, which may offer a promising therapeutic intervention of leonurine in protecting against AS.

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization

“…(Suguro et al, 2018) PPAR γ /LXRα pathway is thought to be involved in the protective role of LEO against atherosclerosis. (Jiang et al, 2017) Encouraged by emerging evidence of its effectiveness and safety in preclinical studies reported by our team and other labs, we have initiated clinical transformation research of LEO since last year. At present, it has passed the safety test of phase I clinical experiment.…”

Isoquinoline Alkaloids and Indole Alkaloids Attenuate Aortic Atherosclerosis in Apolipoprotein E Deficient Mice: A Systematic Review and Meta-Analysis

“…Four of these studies were excluded because atherosclerosis lesion area was not reported (Ching et al, 2013 ; Wang et al, 2015 ; Li et al, 2016 ; Yang et al, 2017 ), one study was excluded because a mixture of herbal medicines was administered (Ho et al, 2012 ), and one study was excluded for intervention combining with surgery (Son et al, 2012 ). At last, 14 eligible studies were included in this systematic review (Wang et al, 2011 ; Ching et al, 2012 ; Fujiwara et al, 2012 ; Mercer et al, 2012 ; Cai et al, 2013 ; Wei et al, 2013 ; Zhuang et al, 2013 ; Chen et al, 2014 ; Xu et al, 2014 ; Feng et al, 2017a , b ; Jiang et al, 2017 ; Liu et al, 2017 ; Zhu et al, 2018 ), of which studies (total 21 animal experiments and 331 animals involved) could be embodied in the meta-analysis (Figure 1 ).…”

“…Only three studies used female animals, eight used male, and three studies didn't mention the gender of animals in their experiments. Mice received a normal-chow diet in five studies (Ching et al, 2012 ; Fujiwara et al, 2012 ; Mercer et al, 2012 ; Wei et al, 2013 ; Jiang et al, 2017 ); a high fat diet in nine studies containing either 21% fat and 1.25% cholesterol (Feng et al, 2017a , b ), 42% fat and 0.2% cholesterol (Zhu et al, 2018 ), 32% fat and 1% cholesterol (Chen et al, 2014 ), 20% fat and 0.15% cholesterol (Xu et al, 2014 ), 16.6% fat, 10.6% sucrose and 1.3% cholesterol (Zhuang et al, 2013 ), the D12079B diet (Research Diets Inc,), containing 21% fat and 0.21% cholesterol (Wang et al, 2011 ), the D12108C diet (Research Diets Inc,), containing 20% fat and 1.25% cholesterol (Cai et al, 2013 ), and unmarked fat and cholesterol content (Liu et al, 2017 ). Administration timing and duration of alkaloids varied greatly.…”

LncRNA AC096664.3/PPAR‐γ/ABCG1‐dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis

“…ABCG1 increases the availability of cholesterol to a variety of extracellular lipoprotein acceptors, including HDL and LDL . A series of studies have shown that ABCG1 can regulate cellular cholesterol efflux, and decreased ABCG1 in atherosclerotic lesions aggravates lipid accumulation and leads to foam cell formation . Ox‐LDL reduces ABCG1 expression in VSMCs, although its mechanism needs to be further explored .…”