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  • Title: Leonurine improves atherosclerosis by activating foam cell autophagy and metabolic remodeling via METTL3-mediated AKT1S1 mRNA stability modulation.
    Author: Yu X, Zhang Y, Wang J, Wang X, Chen X, Yin K, Zhu X.
    Journal: Phytomedicine; 2024 Nov; 134():155939. PubMed ID: 39214016.
    Abstract:
    BACKGROUND: Atherosclerosis (AS) is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Leonurine (LEO) is a unique alkaloid compound with protective effects on the cardiovascular system. However, the exact mechanisms underlying its cardiovascular-protecting action are still not fully elucidated. The methyltransferase 3 (METTL3), the catalytic core of the N6-methyladenosine modification (m6A) methyltransferase complex, has been shown to inhibit autophagy and exacerbate the process of AS via regulation of m6A modification of mRNA. PURPOSE: We aimed to determine whether the inhibited effect of LEO on AS is related to METTL3-mediated AKT1S1 stability. METHODS: The apolipoprotein E (ApoE) knockout mice was subjected to a high-fat diet (HFD), and THP-1 derived macrophages was exposed to oxidized low-density lipoprotein (ox-LDL), to establish the animal and cellular models of AS, respectively. RESULTS: We found that LEO effectively improved AS and reduced the plaque area and inflammation via diminishing macrophage lipid accumulation and remodeling the lipid metabolism profile. LEO activated ox-LDL-induced macrophage autophagy, enhancing lipid metabolism decrease, according to the lipidomic and molecular biology analyses. Additionally, LEO caused a marked increase in autophagy marker levels in mouse models with advanced AS. Furthermore, we found that LEO reactivated autophagy and reversed lipid accumulation by suppressing METTL3 expression. The m6A-seq from ox-LDL-induced macrophages showed that a total of five autophagy-related mRNA transcripts (AKT1S1, AKT1, RB1CC1, CFLAR, and MTMR4) were altered, and AKT1S1 was significantly upregulated by LEO. Mechanistically, LEO-mediated regulation of METTL3 decreased AKT1S1 expression by attenuating its mRNA stability. Silencing AKT1S1 inhibited LEO-METTL3 axis-mediated autophagy and enhanced lipid accumulation in ox-LDL-induced macrophages. CONCLUSION: The study first revealed that LEO exerts anti-atherosclerotic effect by activating METTL3-mediated macrophage autophagy in vivo and in vitro. The mechanism of LEO was further found to be the enhancement of METTL3-mediated AKT1S1 stability to activate autophagy thereby reducing lipid accumulation. This study provides a new perspective of natural medicines on the treatment of AS via an epigenetic manner.
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