Xu Zhengqi, Jiang Feng, Wu Xiaofan, Ren Bowen, Zhang Cuntai, Lin Li, Li Sheng
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
Biomolecules. 2025 Mar 3;15(3):364. doi: 10.3390/biom15030364.
The key fatty acid β-oxidation protein acetyl-CoA acyltransferase 2 (ACAA2) plays a significant role in myocardial lipid peroxidation and cardiac dysfunction induced by renal insufficiency. However, the mechanisms of lipid metabolism related to renal insufficiency-associated cardiac dysfunction remain poorly understood, and current clinical treatments have been largely ineffective. Through analysis of the Gene Expression Omnibus (GEO) database, we identified that the cardiac functional changes caused by renal insufficiency were primarily centered around the fatty acid β-oxidation signaling pathway, where ACAA2 plays a pivotal role in fatty acid β-oxidation, the tricarboxylic acid cycle, and ketone body metabolism. In an adenine-induced renal insufficiency mouse model, further examination with hematoxylin-eosin staining, Masson staining, and Oil Red O staining revealed alterations in the heart and kidney as well as the accumulation of lipid. Non-invasive blood pressure measurements and ultrasound images demonstrated improvements of peripheral vascular and right ventricular hemodynamic parameters with S-nitroso-L-cysteine (CSNO) inhalation therapy. In cell experiments, knocking down ACAA2 led to accumulation of lipid droplets and exacerbation of oxidative stress in cardiomyocytes, while overexpression of ACAA2 reversed these effects. The transcription factor FOXO4 was found to regulate lipid peroxidation by modulating ACAA2, and knocking down FOXO4 partially restored the expression of ACAA2, reducing oxidative stress in cardiomyocytes. Furthermore, exogenous CSNO effectively restored the expression of ACAA2 and reduced the level of FOXO4, thereby mitigating lipid peroxidation and improving cardiac function. Therefore, in the context of renal insufficiency, regulating the FOXO4-ACAA2 axis through CSNO inhalation therapy may provide a novel therapeutic strategy for alleviating myocardial lipid peroxidation and improving cardiac function.
关键脂肪酸β氧化蛋白乙酰辅酶A酰基转移酶2（ACAA2）在肾功能不全诱导的心肌脂质过氧化和心脏功能障碍中起重要作用。然而，与肾功能不全相关的心脏功能障碍的脂质代谢机制仍知之甚少，目前的临床治疗大多无效。通过对基因表达综合数据库（GEO）的分析，我们发现肾功能不全引起的心脏功能变化主要集中在脂肪酸β氧化信号通路，其中ACAA2在脂肪酸β氧化、三羧酸循环和酮体代谢中起关键作用。在腺嘌呤诱导的肾功能不全小鼠模型中，苏木精-伊红染色、Masson染色和油红O染色进一步检查显示心脏和肾脏发生改变以及脂质蓄积。无创血压测量和超声图像显示吸入S-亚硝基-L-半胱氨酸（CSNO）治疗可改善外周血管和右心室血流动力学参数。在细胞实验中，敲低ACAA2导致心肌细胞中脂滴蓄积和氧化应激加剧，而ACAA2过表达则逆转了这些效应。发现转录因子FOXO4通过调节ACAA2来调节脂质过氧化，敲低FOXO4可部分恢复ACAA2的表达，降低心肌细胞中的氧化应激。此外，外源性CSNO有效恢复了ACAA2的表达并降低了FOXO4的水平，从而减轻脂质过氧化并改善心脏功能。因此，在肾功能不全的情况下，通过吸入CSNO治疗调节FOXO4-ACAA2轴可能为减轻心肌脂质过氧化和改善心脏功能提供一种新的治疗策略。
