Lv Fuyou, Qi Ning, Liu Chang, Wang Lili, Dai Tianning, Tian Hai
Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Department of Thoracic surgery, The First Hospital of Harbin, Heilongjiang, China; Future Medical laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Department of Thoracic surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Cell Signal. 2025 Mar;127:111618. doi: 10.1016/j.cellsig.2025.111618. Epub 2025 Jan 23.
Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.
An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined.
DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4.
DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.
二氯乙酸（DCA）在调节细胞代谢和炎症方面已显示出潜力，尤其是在心脏疾病中。本研究调查了DCA在心肌梗死（MI）小鼠模型中的保护作用，重点关注其增强心脏功能、减轻炎症以及将巨噬细胞极化从促炎的M1型转变为抗炎的M2型的能力。
通过结扎左冠状动脉前降支建立急性心肌梗死模型。将小鼠分为四组：正常对照组、MI对照组、MI + 50 mM DCA组和MI + 100 mM DCA组。通过苏木精-伊红（H&E）染色评估心脏纤维化和损伤。通过超声心动图评估心脏功能，并测量血清肌酸激酶-MB（CK-MB）和乳酸脱氢酶（LDH）水平。通过免疫组织化学、酶联免疫吸附测定（ELISA）、蛋白质印迹法和流式细胞术分析心脏组织和RAW264.7细胞中的炎症和凋亡情况。此外，还检测了巨噬细胞极化和相关信号通路。
DCA显著改善了MI小鼠的心脏功能，表现为心肌损伤减轻以及CK-MB和LDH水平降低。它还降低了炎性细胞因子（肿瘤坏死因子-α、白细胞介素-6和白细胞介素-1β），并促进了巨噬细胞从M1型向M2型极化。蛋白质印迹法显示，DCA抑制诱导型一氧化氮合酶（iNOS）和环氧化酶2（COX2），同时增强精氨酸酶1（Arg1）表达，还改善了线粒体功能并减少了凋亡。此外，通过向MI小鼠注射腺相关病毒-PDHK4（丙酮酸脱氢酶激酶），我们发现DCA通过抑制PDHK4有效抑制了MI的进展。
DCA通过增强心脏功能、减轻炎症和促进巨噬细胞极化来保护心肌梗死，可能是通过抑制PDHK4和核因子κB（NF-κB）途径实现的，这使其成为MI后心脏修复的潜在治疗策略。
