Medical School, Nantong University, 226000 Nantong, Jiangsu, China.
Department of Cardiology, Affiliated Hospital of Nantong University, 226000 Nantong, Jiangsu, China.
Front Biosci (Landmark Ed). 2024 Jul 24;29(7):267. doi: 10.31083/j.fbl2907267.
Heart failure (HF) is a clinical syndrome that seriously endangers human health and quality of life as the terminal stage of cardiovascular diseases. Ferroptosis as a new iron-dependent programmed cell death mode that is closely related to the occurrence and development of cardiovascular diseases. Dihydroorotate dehydrogenase (DHODH) has been found to play a crucial role in inhibiting ferroptosis and improving mitochondrial function, and its expression can be upregulated by estradiol (E2). Recent studies have found that DHODH can inhibit ferroptosis by reducing coenzyme Q (CoQ) to CoQH2. Therefore, this study aims to explore the effect of up-regulation of DHODH on the pathological hypertrophy and fibrosis of heart failure and its mechanisms.
The mouse heart failure model was established by transverse aortic constriction (TAC), surgery in mice. Two days after the operation, a subcutaneous injection of E2 or the same volume of sesame oil was given for 8 weeks. Then, the left ventricular systolic function related indicators of mice were measured by echocardiography, and the degree of myocardial fibrosis of mice was detected by histological analysis; the expression levels of heart failure markers were detected by quantitative polymerase chain reaction (q-PCR) and western blot (WB) analysis; the morphological changes of mitochondria in cardiac cells of mice were observed by transmission electron microscopy. Cell model were established by stimulating with phenylephrine for 96 hours. Ferroptosis markers were detected by kits and WB analysis. Mitochondrial function was verified by a JC-1 fluorescent probe, and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The knockdown results were detected by WB analysis after transfection of small interfering RNA (siRNA) of CoQ. Fer-1 was added as a positive control to verify the ferroptosis-related changes of myocardial cells.
In the animal model, we found that E2 treatment alleviates TAC-induced cardiac hypertrophy and fibrosis and suppresses cardiomyocyte ferroptosis by promotes DHODH upregulation in murine cardiomyocytes. In the cell model, DHODH upregulation protects against phenylephrine-induced cardiomyocytes with failure. However, the effect on up-regulating DHODH was inhibited by transfection to down-regulate CoQ expression.
The up-regulation of DHODH could effectively ameliorate the manifestations of heart failure such as myocardial hypertrophy and fibrosis in mice after TAC surgery, inhibit ferroptosis of cardiac myocytes, and ameliorate mitochondrial function. The mechanism involves CoQ-related biological processes.
心力衰竭（HF）是一种严重危害人类健康和生活质量的临床综合征，是心血管疾病的终末阶段。铁死亡作为一种新的铁依赖性程序性细胞死亡模式，与心血管疾病的发生发展密切相关。二氢乳清酸脱氢酶（DHODH）已被发现可通过抑制铁死亡和改善线粒体功能来发挥关键作用，其表达可被雌二醇（E2）上调。最近的研究发现，DHODH 可以通过将辅酶 Q（CoQ）还原为 CoQH2 来抑制铁死亡。因此，本研究旨在探讨上调 DHODH 对心力衰竭病理性肥大和纤维化的影响及其机制。
通过横主动脉缩窄（TAC）手术建立小鼠心力衰竭模型，术后第 2 天，皮下注射 E2 或等体积芝麻油 8 周。然后通过超声心动图测量小鼠左心室收缩功能相关指标，组织学分析检测小鼠心肌纤维化程度；通过定量聚合酶链反应（q-PCR）和蛋白质印迹（WB）分析检测心力衰竭标志物的表达水平；通过透射电子显微镜观察小鼠心肌细胞中线粒体的形态变化。用苯肾上腺素刺激 96 小时建立细胞模型，通过试剂盒和 WB 分析检测铁死亡标志物。通过 JC-1 荧光探针和 2'，7'-二氯二氢荧光素二乙酸酯（DCFH-DA）染色验证线粒体功能。用小干扰 RNA（siRNA）转染后通过 WB 分析检测 CoQ 的敲低结果。加入 Fer-1 作为阳性对照验证心肌细胞的铁死亡相关变化。
在动物模型中，我们发现 E2 处理通过促进小鼠心肌细胞中 DHODH 的上调，减轻 TAC 诱导的心脏肥大和纤维化，并抑制心肌细胞铁死亡。在细胞模型中，DHODH 的上调可防止苯肾上腺素诱导的心肌细胞衰竭。然而，用转染下调 CoQ 表达来抑制上调 DHODH 的作用。
DHODH 的上调可有效改善 TAC 手术后小鼠心力衰竭的表现，如心肌肥大和纤维化，抑制心肌细胞铁死亡，改善线粒体功能。该机制涉及 CoQ 相关的生物学过程。
