背景:左心室舒张功能障碍(LVDD)是心力衰竭的表现,其发病率和患病率每年都在增加。目前,LVDD没有药物治疗,强调迫切需要新的治疗发现。人参皂苷常用于心血管治疗。以前的研究已经合成了人参皂苷前体分子,20S-O-Glc-DM(C20DM),通过生物合成。C20DM显示出更高的生物利用度,生态友好,与传统人参皂苷相比,成本效益高,将其定位为治疗LVDD的有希望的选择。
目的:本研究首先记录了C20DM对LVDD的治疗活性,并揭示了其潜在的作用机制。为C20DM作为一种新的心血管治疗药物提供了药理学基础。
方法:在本研究中,建立小鼠LVDD模型和ISO诱导的H9C2细胞损伤模型。细胞活力,ROS和Ca2+水平,线粒体膜电位,在体外实验中评估了与线粒体生物发生和自噬相关的蛋白质。动物实验包括给药3周,以验证C20DM的治疗效果及其对线粒体和自噬的影响。
结果:研究表明C20DM在治疗LVDD方面比美托洛尔更有效,显着降低E/A比率,e\'/a\'比率,和IVRT,改善心肌炎症和纤维化。C20DM影响PGC-1α的活性,下调PINK1和Parkin,从而加强线粒体质量控制,恢复线粒体氧化呼吸和膜电位。此外,C20DM通过AMPK-mTOR-ULK1通路减少心肌细胞过度自噬,减少心肌细胞肥大和损伤。
结论:总体而言,我们的研究表明,C20DM有可能通过调节线粒体质量控制和细胞自噬来增强LVDD,使其成为心力衰竭治疗的一个有希望的选择。
BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is a manifestation of heart failure, with both its incidence and prevalence increasing annually. Currently, no pharmacological treatments are available for LVDD, highlighting the urgent need for new therapeutic discoveries. Ginsenosides are commonly used in cardiovascular therapy. Previous research has synthesized the ginsenoside precursor molecule, 20S-O-Glc-DM (C20DM), through biosynthesis. C20DM shows greater bioavailability, eco-friendliness, and cost-effectiveness compared to traditional ginsenosides, positioning it as a promising option for treating LVDD.
OBJECTIVE: This study firstly documents the therapeutic activity of C20DM against LVDD and unveils its potential mechanisms of action. It provides a pharmacological basis for C20DM as a new cardiovascular therapeutic agent.
METHODS: In this study, models of LVDD in mice and ISO-induced H9C2 cell damage were developed. Cell viability, ROS and Ca2+ levels, mitochondrial membrane potential, and proteins associated with mitochondrial biogenesis and autophagy were evaluated in the in vitro experiments. Animal experiments involved administering medication for 3 weeks to validate the therapeutic effects of C20DM and its impact on mitochondria and autophagy.
RESULTS: Research has shown that C20DM is more effective than Metoprolol in treating LVDD, significantly lowering the E/A ratio, e\'/a\' ratio, and IVRT, and ameliorating myocardial inflammation and fibrosis. C20DM influences the activity of PGC-1α, downregulates PINK1 and Parkin, thereby enhancing mitochondrial quality control, and restoring mitochondrial oxidative respiration and membrane potential. Furthermore, C20DM reduces excessive autophagy in cardiomyocytes via the AMPK-mTOR-ULK1 pathway, diminishing cardiomyocyte hypertrophy and damage.
CONCLUSIONS: Overall, our research indicates that C20DM has the potential to enhance LVDD through the regulation of mitochondrial quality control and cellular autophagy, making it a promising option for heart failure therapy.