Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, Rome, Italy.
Cardiovasc Res. 2023 Dec 19;119(16):2653-2662. doi: 10.1093/cvr/cvac184.
The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter 1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI).
We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HSs). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells when compared with CCS patients (P < 0.0001; P = 0.0101, respectively) and HSs (P = 0.0071; P = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (P = 0.0005 for nuclear vs. cytoplasm localization), while in CCS and HS, it was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared with HS (P = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1-mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the down-regulation of pro-inflammatory cytokine expression.
NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.
免疫细胞的功能能力强烈依赖于其代谢状态，炎症反应的特征是免疫细胞中葡萄糖的利用率增加。本研究旨在确定葡萄糖代谢及其参与者（葡萄糖转运蛋白 1（GLUT-1）和丙酮酸激酶同工酶 M2（PKM2））在非 ST 段抬高型心肌梗死（NSTEMI）患者中观察到的适应性免疫和炎症失调中的作用。
我们招募了 248 名患者，将其分为三组：NSTEMI 患者、慢性冠脉综合征（CCS）患者和健康受试者（HSs）。与 CCS 患者（P < 0.0001；P = 0.0101）和 HSs（P = 0.0071；P = 0.0122）相比，NSTEMI 患者的 T 细胞中 GLUT-1 表达更高，葡萄糖摄取也增加（P < 0.0001；P = 0.0101）。PKM2 在 NSTEMI 的 T 淋巴细胞中主要定位于核内（核内与细胞质内定位相比，P = 0.0005），而在 CCS 和 HS 中，它在两个隔室中均匀分布。此外，与 HS 相比，NSTEMI 中的 PKM2 核分数明显更高（P = 0.0023）。在 NSTEMI 患者中，Shikonin 和 Fasentin 的治疗分别抑制 PKM2 酶活性和 GLUT-1 介导的葡萄糖内吞作用，导致 GLUT-1 表达显著降低，同时促炎细胞因子表达下调。
NSTEMI 患者表现出 GLUT-1/PKM2 代谢环的失调，其特征是 PKM2 的核易位，在那里它作为促炎基因的转录调节剂起作用。这种有害的循环可能代表个性化医学的新治疗靶点。
