Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410000, China.
Redox Biol. 2022 Jun;52:102313. doi: 10.1016/j.redox.2022.102313. Epub 2022 Apr 13.
Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.
循环中甘氨酸水平降低与心血管疾病（CVD）密切相关，但甘氨酸在动脉粥样硬化（大多数 CVD 的根本原因）中的因果作用和治疗潜力仍有待确定。在这里，在确定患有严重冠状动脉疾病（sCAD）的患者循环甘氨酸水平降低后，我们通过调节易患动脉粥样硬化的小鼠中的甘氨酸可利用性来研究甘氨酸在动脉粥样硬化中的因果作用。我们进一步评估了最近发现的具有双重脂质/葡萄糖降低特性的甘氨酸基化合物 DT-109 的抗动脉粥样硬化潜力。甘氨酸缺乏会增强，而甘氨酸补充会减弱载脂蛋白 E 缺陷（Apoe）小鼠的动脉粥样硬化发展。DT-109 治疗显示出最显著的抗动脉粥样硬化作用，并降低了整个主动脉树和主动脉窦的动脉粥样硬化，同时减少了超氧化物。在已患有动脉粥样硬化的 Apoe 小鼠中，DT-109 治疗可显著降低动脉粥样硬化和主动脉超氧化物，而不降低脂质水平。靶向代谢组学和动力学研究表明，DT-109 在单核细胞中诱导谷胱甘肽形成。在骨髓来源的巨噬细胞（BMDMs）中，甘氨酸和 DT-109 可减轻甘氨酸缺乏引起的超氧化物形成。在谷氨酰胺半胱氨酸连接酶修饰亚基缺陷（Gclm）小鼠的 BMDMs 中，谷胱甘肽生物合成受损，这种作用被消除，Gclm 小鼠的 BMDMs 中缺乏谷氨酰胺半胱氨酸连接酶修饰亚基。代谢通量和碳示踪实验表明，甘氨酸缺乏抑制 BMDMs 中的谷胱甘肽形成，而基于甘氨酸的治疗方法可诱导新的谷胱甘肽生物合成。通过结合 CAD 患者的研究、使用动脉粥样硬化小鼠的体内研究以及使用巨噬细胞的体外研究，我们证明了甘氨酸在动脉粥样硬化中的因果作用，并确定了基于甘氨酸的治疗方法是通过诱导谷胱甘肽生物合成介导的抗氧化作用来减轻动脉粥样硬化的一种方法。
