Zampas Paraskevas, Li Zhen, Katsouda Antonia, Varela Aimilia, Psarras Stelios, Davos Constantinos H, Lefer David J, Papapetropoulos Andreas
Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation Academy of Athens, Greece; Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece.
Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Pharmacol Res. 2025 Jan;211:107542. doi: 10.1016/j.phrs.2024.107542. Epub 2024 Dec 10.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that occur concurrently and increase the risk of cardiovascular disease. 3-mercaptopyruvate sulfurtransferase (MPST) is a cysteine-catabolizing enzyme that yields pyruvate and hydrogen sulfide (HS) and plays a central role in the regulation of energy homeostasis. Herein, we seek to investigate the role of MPST/HS in MetS and its cardiovascular consequences using a mouse model of the disease. Mice were fed a high-fat diet (HFD) for 15 weeks to induce obesity and hyperglycemia and administrated a nitric oxide synthase inhibitor, during the last 5 weeks to induce hypertension and MetS. This model caused a mild left ventricular (LV) diastolic dysfunction and vascular endothelial dysfunction. Free HS and sulfane-sulfur levels were decreased in the aorta, but unaltered in the heart. Also, downregulation of MPST and thiosulfate sulfuretransferase (TST) were observed in the aorta. Global deletion of Mpst (Mpst) resulted in increased body weight and greater glucose intolerance in mice with MetS, without affecting their blood pressure, and caused an upregulation of genes involved in immune responses in the vasculature suggestive of T-cell infiltration and activation. Pharmacological restoration of HS levels ameliorated the comorbidities of MetS; GYY4137 administration reduced body weight and blood pressure, attenuated cardiac fibrosis and improved glucose handling and endothelium-dependent relaxation. In conclusion, this study found that reduced MPST/HS exacerbates the pathological changes associated with MetS and contributes to vascular inflammation. HS supplementation emerges as a potential therapeutic approach to treat the abnormalities associated with MetS.
代谢综合征（MetS）是一组同时出现的代谢异常情况，会增加心血管疾病的风险。3-巯基丙酮酸硫转移酶（MPST）是一种分解半胱氨酸的酶，可产生丙酮酸和硫化氢（HS），并在能量稳态调节中起核心作用。在此，我们试图使用该疾病的小鼠模型来研究MPST/HS在MetS及其心血管后果中的作用。给小鼠喂食高脂饮食（HFD）15周以诱导肥胖和高血糖，并在最后5周给予一氧化氮合酶抑制剂以诱导高血压和MetS。该模型导致轻度左心室（LV）舒张功能障碍和血管内皮功能障碍。主动脉中游离HS和硫烷硫水平降低，但心脏中未改变。此外，在主动脉中观察到MPST和硫代硫酸盐硫转移酶（TST）的下调。Mpst（Mpst）的整体缺失导致患有MetS的小鼠体重增加和葡萄糖耐量降低，而不影响其血压，并导致血管中参与免疫反应的基因上调，提示T细胞浸润和激活。HS水平的药理学恢复改善了MetS的合并症；给予GYY4137可减轻体重和血压，减轻心脏纤维化，并改善葡萄糖处理和内皮依赖性舒张。总之，本研究发现MPST/HS降低会加剧与MetS相关的病理变化，并导致血管炎症。补充HS成为治疗与MetS相关异常的一种潜在治疗方法。
